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WHO Technical Report Series

917

WHO EXPERT COMMITTEE

ON SPECIFICATIONS FOR

PHARMACEUTICAL PREPARATIONS

Thirty-eighth report

World Health OrganizationGeneva

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1. Introduction

The WHO Expert Committee on Specifications for PharmPreparations met in Geneva from 10 to 14 March 2003Asamoa-Baah, Executive Director, Health Technology and

ceuticals, welcomed the Committee members and other paon behalf of the Director-General, Dr Gro Harlem Brundt

In his opening remarks Dr Asamoa-Baah explained that sincmeeting of the Committee there had been more evidencglobalization and harmonization of specifications for pharmpreparations in general, and for pharmaceuticals used in tment of HIV, tuberculosis and malaria, in particular. He that WHO was committed to helping to ensure the quality of

ceuticals and to treating HIV, tuberculosis and malaria. Hthat although some patients were fortunate in having easy drugs, others were less so. However, there was cause for owith the creation of alliances to finance measures to fight HIculosis and malaria. Dr Asamoa-Baah also highlighted the prcounterfeit medicines which appeared to be greater than hnally been feared, and he emphasized the necessity for morbe paid to this problem. The issue of quality and safety of ph

ticals required appropriate attention.

The Committee was briefed on the WHO strategy for mediits focus on increasing access to quality medicines. He mentithe 20th century had been a period during which medical ment had led to improved life expectancy, but that there wbetween potential and reality due to lack of access to qualcines. The Committee was also informed of the nomination o

Lee from the Republic of Korea, to replace Dr BrundtlanDirector-General of WHO. Dr Lee had been involved in thprogramme and will assume his new position in July 2003. Hnation coincided with the forthcoming period of consolidatishould result in better links between policy decisions and imtation of WHO activities. Medicine was a priority area in

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rational use and policy development, which will put norms dards in place to accomplish these objectives.

The Committee was informed about the wide range of undertaken by the Quality Assurance and Safety: Medicineteam. They were told of the need to continue work relati

quality of medicines at WHO and to run activities in parallthere would be more rapid benefits at country level. Positivehad already been seen but there was still much to be accomCounterfeiting continued to be a major problem. The nexttional Conference of Drug Regulatory Authorities (ICDRAuled for 2004 in Madrid, Spain would include a pre-comeeting on counterfeit drugs which would be open to relevanThe Committee was informed about the new activities r

the model quality assurance for procurement and to papproaches in setting priorities. The safety of certain drugsa concern and required investigation. There had been icollaboration in the area of quality assurance of medicines wHealth Technology and Pharmaceuticals Cluster, with othein WHO and with outside partners.

2. General Policy

2.1 Tenth International Conference of Drug RegulatoryAuthorities, China, Hong Kong, Special Administrative

Conference reports and recommendations made to the counto WHO were made available to the Committee. The Comminformed that the next ICDRA would be held in Madrid,2004, when a special session dedicated to pharmacopoeias proposed. In addition a pre-conference meeting on counterwas planned.

2.2 Side meeting to the tenth International Conference of Regulatory Authorities

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3. to encourage international harmonization efforts by develop common specifications and international standards, with special focus on medicines for which nocopoeial monographs currently exist, e.g. new drug entcombinations or priority disease programmes of majo

impact;4. to make every effort to help combat counterfeit drugs;5. to reinforce the close links between regulatory author

pharmacopoeias; and6. to discuss the importance of impurity profiles and lim

international level, especially for internationally tradedmaterials.

2.3 International Conference on Harmonisation

WHO is an observer to the International Conference on isation (ICH) and liaises with non-ICH countries by distribformation about ICH Guidelines. The Committee was with a paper entitled “The impact of implementation of IClines in non-ICH countries”. This report includes the issues rthe application of ICH quality documents to generic drugs. Tmittee was provided with an update on the new ICH guid

impurities and stability testing.The Committee endorsed the collaboration between WICH, especially WHO’s participation in the working groups quality.

2.4 Pharmacopoeial Discussion Group1

The Committee was updated on the collaboration between Wthe Pharmacopoeial Discussion Group (PDG). WHO hapated as an observer at the last three PDG meetings. The ning is scheduled to be held in Brussels, Belgium in July 200

2.5 Counterfeit drugs

The Committee was informed about the increasing problem

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widespread problem. In addition, a new project in Asian counder way to study the situation in the national context. standing the difficulties identified, the Committee re-endorecommendation made in its previous report (1).

2.6 Traditional medicine

The Committee was presented with a progress report onwork related to herbal medicine and which introduced thTraditional Medicines Strategy: 2002–2005 for which the foobjectives are:

— framing policy;— enhancing safety/efficacy/quality;

— ensuring access; and— promoting rational use.

Several new technical documents on herbal medicines had bduced and had been circulated for comments before their finwhile other finalized documents had been translated intolanguages.

The Committee noted that in some countries herbal medici

ucts were considered as food or as dietary supplements regulation might therefore be different from that of normalceutical products.

Members offered their support for the implementation ofguidance documents the subjects of which included safety mand quality assurance.

The Committee was informed that resolution EB 111.R12

tional medicine had been recommended by the one-huneleventh session of the WHO Executive Board for adoptififty-sixth World Health Assembly in May 2003.

The Committee commended the good work undertaken bythis area and encouraged its continuation.

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mended the use of combination drugs as more appropriate. Hquality standards for these combinations might not exist in tdomain. It had therefore been recommended by experts onthat the development of specifications for quality control sexpedited. The Committee expressed concern that fixed-do

nation drug products were more complicated to manufacanalyse. In some cases the information available about theefficacy and quality was inadequate. The Committee was cerned about the results of a study undertaken in the subregion that reported on the distribution of substandard qucounterfeit antimalarial products.

The Committee urged the WHO Secretariat to address thnent issues.

2.8 Biologicals

The Committee was informed about a current joint effort win the area of vaccines to assess the capacity of some nationtory agencies and to identify their needs. One of the majorcies identified so far in the assessment had been in thepostmarket surveillance monitoring. Another example of c

tion with the Expert Committee on Biological Standardizaits technical advice to the International NonproprietaryProgramme.

2.9 Risk related to transmissible spongiform encephalopa

The Committee was informed of the results of the WHO conheld in February 2003 on transmissible spongiform enceph(TSE) and indicated that the main concerns with this diseastransmission from animals to humans and possibly from hhuman. There were links between variant Creutzfeldt-Jako(vCJD) and bovine spongiform encephalopathy (BSE). Tbeen fewer cases of BSE reported in recent years in thKingdom as a result of precautionary measures, whereas inof Europe and other parts of the orld the trend as in

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possibility of applying WHO’s rapid alert system to starting had also been discussed.

2.10 Bioequivalence

The Committee was presented with the first results on comdissolution testing studies, using in vitro testing under condimay be used to indicate bioequivalence. The subjects of dincluded bioequivalence studies for fixed-dose combination the difficulty in conducting bioequivalence studies in some cthe need for proper guidance; and the possibility of phbioequivalence requirements for certain drugs or of waivinbioequivalence requirements for some dosage forms (e.gbased on existing knowledge.

The Committee acknowledged the good guidance provided and the need to apply a risk analysis-based approach in thbioequivalence. Future work should include the review and current guidance, noting that in vitro dissolution testing considered as an indicator of possible bioequivalence probl

Bioequivalence is significant only if compliance with goofacturing practices and sourcing of active pharmaceutic

dients (API) are well controlled. The Committee endorsed for a review and an update of the existing WHO guidebioequivalence.

3. Quality control — specifications and tests

3.1 The International Pharmacopoeia

Volume 5 of the third edition of The International Pharmac

now available. The Committee was informed that revision othe general methods of The International Pharmacopoeia deother volumes, as well as the development of new methneeded. It is intended that the amendments made to prevumes will be incorporated in an updated version to be made

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Scheme (BCS) class I drugs”, was presented to the Commimethods include a recommended test procedure for inclusio

International Pharmacopoeia.

The Committee praised this work. It recommended that tment be circulated for comments and for validation of the pmethods prior to its adoption.

3.3 Specifications for radiopharmaceuticals

The representative of the International Atomic Energy(IAEA) presented an update of the joint effort of WHOIAEA in radiopharmaceuticals, as well as a draft report of thtation on monographs and specifications for radiopharma

held in Geneva on 16–17 December 2002. It was reportedexpert group had recommended that the general mecontained in the third edition of Volume 1 of The Inte

Pharmacopoeia be replaced with the revised version.

The Committee endorsed the recommendation and alsomended that work commence on the specific monographs.

3.4 Quality specifications for antituberculosis drugs

The Committee was presented with a status report on wortaken on methods for conducting screening tests and specfor antituberculosis drugs that were currently being develovalidated entitled “Quality specifications for antituberculos

The Committee recommended that this work should contin

3.5 Quality specifications for antimalarials

The Committee received a status report on work carriescreening test methods and specifications for antimalarials tcurrently being developed and validated entitled “Quality ti n f ntim l i l ” R f n m d t V l m 5 f

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The Committee commended the availability and quality of tgraphs on antimalarials published in Volume 5 of The Inte

Pharmacopoeia and recommended that the work be continalso section 2).

3.6

Pharmacopoeial monographs on antiretroviralsThe Committee was provided with a document entitled specifications for antiretrovirals” which described work beinout on the development of specifications of certain antirdrugs. This project was developed as a result of a recommmade by the Expert Committee at its thirty-seventh meeof the tremendous political pressure to make quality antiagents more readily available to disadvantaged HIV-positive

It was indicated that when these monographs become availshould be widely distributed for further consultation and va

The Committee expressed its support for the work and askkept informed of its progress and results.

3.7 Quality control — specifications for excipients

The Committee was informed of the work in progress by the

copoeial Discussion Group (PDG) on harmonizing specificexcipients. The discussion that followed highlighted the fact texcipients were of a potentially high-risk nature. It was aaccept the offer of the PDG to publish monographs on thoents harmonized to date in the next volume of The Inte

Pharmacopoeia. It was further recommended that WHOindicate differences in tests where they exist, in order to fabetter understanding of the harmonized monographs.

4. Quality control — International ReferenceMaterials

4.1 International Chemical Reference Substances

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edged the opinion of the EDQM representative who clarauditors using ISO 17025 had agreed to consider the practigiving expiry dates as acceptable. General guidelines for the ment, maintenance and distribution of chemical reference sucan be found in the Thirty-fifth report of the Expert Comm

Specifications for Pharmaceutical Preparations ( 2).The report for 2001 was accepted and the Committee exprappreciation of the support given by Apoteket in providreference standards at a minimal cost. Any further creceived on the Centre’s report within the deadline will be foto the Centre for appropriate action.

The Centre’s report for 2002 was circulated for distribufurther comments. A document was presented to the Comma proposal made to disestablish some 13 of these standards ano longer required or requested. In addition, it was recomthat where the reference substances had either been dises(e.g. biological reference materials), or were subject to intecustoms controls, that monographs in The International Ph

poeia be revised.

It was noted that because there would be a delay betw

disestablishment of reference standards and publication ofmonographs, the old standards should be temporarily retaiproposals were accepted.

The Centre for International Chemical Reference Substanccontacted at the following address:

WHO Collaborating Centre for Chemical Reference SubApoteket AB

Produktion & LaboratorierCentrallaboratoriet, ACLPrismavägen 2SE-141 75 Kungens Kurva, SwedenFax: + 46 8 740 60 40 or e-mail: [email protected]

The International Reference Materials available from the

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new technology such as e-mail to transmit spectra. Only conspectra would be discussed at meetings. The proposal was and the Committee acknowledged the contribution of the Wlaborating Centre for International Infrared Reference Zurich, Switzerland. Members expressed their appreciatio

Swiss Federal Institute of Technology for providing the rnecessary for the activities of the Centre.

5. Quality control — national laboratories

5.1 Equipment for model quality control laboratories

The Committee was informed that the document providing

tion on the cost of equipment for model quality control labentitled “Cost estimate of equipment for model quality conratories” was being revised to include the technical specificaeach item of equipment as requested by the Expert Commithirty-seventh meeting.

5.2 External quality assurance assessment scheme

Two documents and the summary report from the Europeatorate for the Quality of Medicines were presented to the CoIt was noted that 36 laboratories, i.e. six in each WHO Regdomly numbered in each report, had participated in this secoof the external quality assessment scheme.

The Committee noted that this was a valuable exercise pinsight into the realities of the proficiency of drug qualitlaboratories. It was also seen as a tool to help laboratories to

their performance by serving as a benchmarking exercise.

The Committee expressed its appreciation of the work drecommended continuation of these efforts. It was furthemended that the names of participating laboratories be inthe list of acknowledgements of the Expert Committee rep

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However, the Committee saw no need to revise the current vthe WHO supplementary GMP for excipients as it was fousatisfactory in its present form ( 3).

6.2 Heating, ventilation and air conditioning

The Committee was provided with the first draft of the supplguidelines on GMP for heating, ventilation and air con(HVAC) systems. The document will enter the consultatioand be included in the agenda of the next meeting of thCommittee.

The Committee commended WHO for its work on this sub

6.3 Herbal medicinal productsThe Committee was informed that a process for the revisiWHO supplementary guidelines for the manufacture omedicinal products had been initiated (4). A modified vthe guidelines would be submitted to the Expert Commitnext meeting. Although some concerns about validationments were expressed, the Committee recommended the retthe validation requirements as an important part of quality a

of drugs. It also stressed the importance of proper packalabelling for these products.

6.4 Validation

The Committee was informed that a new WHO text for a sutary GMP guideline on validation had been prepared and cfor comments. A modified version would be submitted to th

Committee at its next meeting.

6.5 Water for pharmaceutical use

The Committee was informed that the supplementary GMwater for pharmaceutical use was being distributed for co

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7. Quality assurance — inspection

7.1 Strengthening of Pharmaceutical Manufacturing Inspeproject and development of training modules for inspe

A presentation on the Strengthening of Pharmaceutical Maing Inspection (SPMI) project and on the new training recently developed for inspectors was made to the Commit

The aim of the SPMI project was to consolidate and extend achievements of the first project entitled: “Promoting of thmentation of GMP” (1998–2000) and to focus on strengthpharmaceutical manufacturing inspectorates by developing and using the CD-ROM of WHO basic training modules ontotal of 240 participants from 47 countries had undergone th

and about 5800 copies of the CD-ROM had been distribumaterials had been translated into Spanish by the WHO Office for the Americas/Pan American Health Organizationand into Chinese by the State Drug Administration (SDAThe Spanish version had been utilized by PAHO in the RegAmericas, where 571 individuals had received training. The run five training courses during 2002.

Supplementary training modules on the subject of “Val“Water for pharmaceutical use” and “Air handling systems”been developed and were almost ready for distribution.

The efforts undertaken with the SPMI project may assist in pa consistent application of the requirements in the inspeccess. The Committee acknowledged that the project wouldstrengthening and improving the inspection process. Membmended the WHO project staff for their initiative and their s

raising the awareness of GMP around the world.

8. Quality assurance — distribution andtrade-related

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practices (GSP) related to activities, such as repackaging anling, involved in the distribution of starting materials, had becirculated and the resulting comments incorporated. It wnized that the implementation of this guidance could alsoreducing the occurrence of counterfeit drugs. After discuCommittee recommended the adoption of this guidance (Awith some minor additions reflecting the outcome of the dis

8.2 WHO Pharmaceutical Starting Materials Certification Sfor use in international commerce

The Committee considered the new WHO PharmaceuticaMaterials Certification Scheme (SMACS) for which twcertificates were proposed: one for issue by national author

the other for completion by manufacturers of starting mateconcept of this scheme was presented and discussed during ICDRA as suggested by the Expert Committee at its thmeeting.

After a discussion about the implementation of the minimumments by the relevant authorities, it was suggested that theshould be reviewed after a pilot phase. Additionally, QSM

develop training materials on this subject. The Committee supported the proposal and adopted the document for submthe World Health Assembly (Annex 3).

8.3 WHO Certification Scheme on the quality of pharmaceproducts moving in international commerce

The Committee was briefed on the implementation of the swhich about 140 members were participating. The Comm

also briefed on the recommendations made at the ICDRA inthe issue of certificates.

The Committee was informed of some cases where WHO-tycates were issued:

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The Committee agreed that a small working group be fodiscuss the current status of the certification scheme, anmended further measures to improve its effectiveness for tion to the next Expert Committee meeting.

9. Quality assurance — risk analysis

9.1 New approach to inspections and manufacture

Documents related to the use of parametric release and a riskapproach for the inspection process were provided Committee’s information and discussion. It was noted that ciple of risk analysis was being used in a variety of settings a

possibly be used by drug regulatory authorities, especially thlimited resources.

The Committee considered the approach to have value anmended that the issue be reconsidered in the future.

10.

Quality assurance — drug supply10.1 Pre-qualification of manufacturers for the procuremen

sourcing of pharmaceutical products

The Committee was informed of the background and progrWHO procedure for the pre-qualification of suppliers andceutical products ( 5).

The purpose of this procedure was to verify that pharm

products and manufacturers met the specifications and stanby WHO. As an additional benefit, those manufacturers ththis programme would serve as an example to others becmanufacturers that did adopt it would receive internationation. The Committee emphasized the need for preserving tdentiality of information and for selecting competent inspe

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The Committee noted that drug regulatory authorities wbenefit as inspections were carried out by teams of inspectoring those from the Pharmaceutical Inspection Co-operation(PIC/S), signatories, WHO staff and local representatives drug regulatory authority inspectorates of the countries inv

The Committee commended the good work in develodocuments discussed below and acknowledged the need fqualification programme.

10.2 Pre-qualification of quality control laboratories

A draft procedure for assessing the acceptability, in prinquality control laboratories for use by United Nations Agepresented to the Committee. Suggestions for additions to tment were made (e.g. a standard operation procedure ddescribing the infrastructure of the laboratories, etc.). ThCommittee suggested that laboratories that were accepted this suggested procedure could also be used by other countrisame activities. It was recommended that certification un17025 should be taken into consideration when laboratoassessed by WHO.

The Committee accepted, in principle, the text as a workiment. Suggestions made would be taken into considerthe Secretariat and a revised version would be distributed for approval (the final document will be published as a(Annex 4).

Guidelines for drafting a laboratory information file were pto the Committee. The Committee accepted, in principle, tment as a working document. Suggestions made would be t

consideration by the Secretariat and a revised version woutributed by e-mail for approval (the final document will be pas an annex) (Annex 5).

10.3 Pre-qualification of procurement agencies

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The Committee accepted, in principle, the document as adocument. Suggestions made would be taken into considethe Secretariat and a revised version would be distributed for approval (the final document will be published as a(Annex 6).

Guidelines for drafting a procurement agency informationpresented to the Committee and discussed. Suggestions wefor the inclusion of additional information to be submitted onments regarding personnel and storage requirements.

The Committee accepted, in principle, the document as adocument. Suggestions made would be taken into considethe Secretariat and a revised version would be distributed

for approval (the final document will be published as a(Annex 7).

Draft interim guidelines for the assessment of a procuremenwere presented to the Committee and discussed. These interlines would be used during the transition period until the fiment (model quality assurance system) becomes available.

The Committee suggested that the checklist should be cons

basic, some of the criteria be considered as essential, anshould be classed as desirable or expected. The outcome smonitored to assess its impact on the delivery of quality dr

The Committee accepted the document, in principle, as adocument. Suggestions made would be taken into considethe Secretariat and a revised version would be distributed for approval (the final document will be published as a(Annex 8).

The second draft of a model quality assurance system for prcation, procurement, storage and distribution of pharmproducts was considered by the Committee. The Comminformed about the background that led to the developmedocument and received an explanation of the urgent need

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should urge countries to ensure that all pertinent activitieformed in accordance with the relevant guidelines. The bioequivalence, storage conditions and delivery were also the discussion, reflecting their importance for the assurancquality.

The Committee accepted the document, in principle, as a mcould be assessed and modified as necessary. It was furthethat the Secretariat should produce a revised version, taconsideration the comments made during the discussion. Tmittee agreed, on the basis of urgency, to make the revavailable for use as an interim text. As it was anticipateddocument would be finalized before the end of 2003, it waagreed that it would subsequently be presented for inclusi

report of the next meeting of the Expert Committee.

10.4 Pre-qualification procedure for procurement of HIV/AIdrugs

The Committee was informed of WHO’s pilot project, beducted in conjunction with the United Nations Childre(UNICEF), the Joint United Nations Programme on H(UNAIDS), the United Nations Population Fund (UNFwith the support of the World Bank, to test the system forqualification of suppliers of HIV/AIDS drugs. This included

— dossier evaluation;— samples for analysis; and— manufacturing site inspection.

Only manufacturers of dosage forms were subject to inspectithis programme (the manufacturers of active pharmaceutica

ents were not to be inspected at this time, but the possibilitinspections being required in the future was not to be exThe Committee was briefed on the number of quality defectsthe course of this project and recommended that all possibshould be made to ensure budgetary support for its continu

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Internet as well as further computerized processes to facilitacation preparation. The link with the updated pharmacopobase, which is a compilation of monographs available pharmacopoeias, was also mentioned.

The Committee was informed of the workplan, progress an

challenges of this programme. The Committee was also inforpriority continued to be given to upgrading the database arcand functionality.

The Committee noted that a small panel of experts had beeto advise on issues relating to compounds in the area of bin close collaboration with the Expert Committee on BStandardization.

The Committee was also informed of the plans for naming eThe Committee endorsed this plan because the consistent nexcipients would be useful for the GTDP effort.

The Committee was informed about a proposed revisionprocedure for the selection of recommended INNs for pharcal substances” which was under discussion by the Executiv

The Committee commended the close collaboration with t

Expert Committee on Biological Standardization as well ascess of the INN programme, and encouraged their continue

12. Miscellaneous

12.1 Launch of The International Pharmacopoeia , Volume 5

The new volume of The International Pharmacopoeia was p

to the Committee. This document includes 72 new monograwhich are for antimalarials, and contains monographs for arderivatives and their dosage forms for finished products. It wthat no other pharmacopoeia had such complete monographtype of drug. In addition, a number of new test methods an

i t i l d d i thi l Th C itt

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wide of the production, distribution and sale of counterfeit,and substandard pharmaceutical products. In addition towaste of money for the people who buy them, counterfeit standard drugs prolonged treatment periods, exacerbated ttions being treated, led to increased drug resistance and cocause death.

A recommendation was made at the last ICDRA that WHwork with other partners to address these problems jointly.ship was initially envisaged with PIC/S, the International Phtical Federation (FIP) and national pharmacopoeias. The oof the Alliance would be to:

— increase awareness of the importance of the quality, s

efficacy of medicines through advocacy and promotion;— promote assistance to countries to improve their accesquality medicines;

— promote measures to eliminate the manufacture, distribsale of poor quality medicines with special focus on thosthe treatment of life-threatening conditions; and

— promote cooperation between international and nationazations to improve the quality of medicines.

There were presently a number of participants, but there is aity of others joining in the future.

The Committee was in favour of WHO’s efforts to establishAlliance for the Quality of Pharmaceuticals in response to crelating to the quality of medicines.

12.3 WHO Medicines Strategy 2004 –2007

The Committee was presented with the new proposed frfor the WHO Medicines Strategy 2004–2007 on which cwere being sought by 15 May 2003. The document outlined taspects, the challenges envisaged, measures to meet these cand benchmarks for the assessment of achievement. It wa

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objectives of the old plan had been met; this knowledge cohave been used as a measure for the potential success of the nIt was also felt that although provision for training was madocument, greater emphasis on the development of human rwould be desirable, particularly for personnel in communmacies in rural areas, such as chemical vendors, and for pinvolved in GMP and GTDP. Members felt that althougprotection could be an incentive to research and developmedrugs for target diseases, its considerable cost could also bbling block to making drugs available more cheaply to vugroups, and to future research on treatments for HIV/AIDculosis and malaria in developing countries.

Notwithstanding the questions raised, the members were un

in accepting the document as a good working draft. The Corecommended that the WHO Secretariat should take the suinto consideration and re-circulate the revised document fostudy.

Acknowledgements

Special acknowledgement was made by the Committee to Mrs W. BA.N. Castagnuozzo, Dr S. Kopp, Dr L. Rägo and Dr P. Vanbel, Quality and Safety: Medicines, Essential Drugs and Medicines Policy, WHOSwitzerland, who were instrumental in the preparation and proceedmeeting.

The Committee also acknowledged with thanks the valuable contributioits work by the following institutions and persons:

C. Guelbenkian Laboratory of Drug Quality Control, Yerevan, Armenia;Regional Drug Testing Laboratory, Kingston, Jamaica; Central Drugs L

Calcutta, India; Central Laboratory for Quality Control of Medicines of tof Health of Ukraine, Kiev, Ukraine; Central Quality Control Laboratory, SOman; Centre for Quality Assurance of Medicines, Potchefstroom, SoDepartamento de Control Nacional Unidad de control de calidad defarmaceúticos del mercado nacional (Control de Estanteria), SantiagoChile; Bureau of Drug and Narcotic, Department of Medical Sciences, NThailand; Drug Analysis Division, National Pharmaceutical ContrS l M l i F d d D C t l L b t i Mi i t f

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El Control de Calidad de Medicamentos, Montevideo, Uruguay; LaboAnálisis y Asesoría Farmacéutica, San Pedro de Montes de Oca, San JRica; Laboratorio de Normas y Calidad de Medicamentos Caja CostarSeguro Social, Universidad de Costa Rica, San Jose, Costa Rica; LaQuality Control and Standardization of Drugs, Tashkent, Uzbekistan; Lfor Medicine Quality Control, Tbilisi, Georgia; National Drug Quality AssuResearch Laboratory, Damascus, Syrian Arab Republic; National DrAssurance Laboratory, Colombo, Sri Lanka; National Institute for thePharmaceutical and Biological Products, Beijing, People’s RepublicNational Institute of Drug Quality Control, Hanoi, Viet Nam; National LabDrug Quality Control, Phnom Penh, Cambodia; National OrganizatioControl and Research, Agouza, Cairo, Egypt; National Quality Control LNairobi, Kenya; Pharmaceutical Laboratory Centre for Analytical ScienScience Authority, Singapore; Philippine Institute of Pure and Applied Quezon City, Philippines; Provincial Quality Control Laboratory of DrugYogyakarta, Indonesia; Quality Control Laboratory, Health Ministry of KBishkek, Kyrgyzstan; Royal Drug Research Laboratory, Department oministration, Kathmandu, Nepal; WHO Collaborating Centre for Drug Q

trol, Therapeutic Goods Administration Laboratories, Woden, AustralTerritory, Australia; WHO Collaborating Centre for Drug Quality Assutional Institute for the Control of Pharmaceutical and Biological ProductsHeaven, Beijing, People’s Republic of China; WHO Collaborating Biopharmaceutical Aspects of Drug Quality Control, Biopharmaceutictory, University of Clermont-Ferrand, Clermont-Ferrand, France; WHO ing Centre for Drug Information and Quality Assurance, National Pharmacy, Budapest, Hungary; WHO Collaborating Centre for Quality of Essential Drugs, Central Drugs Laboratory, Calcutta, India; WHO CoCentre for Quality Assurance of Essential Drugs, National Quality Cont

tory of Drug and Food, Directorate General of Drug and Food Control,Health, Jakarta, Indonesia; WHO Collaborating Centre for RegulatoryPharmaceuticals, National Pharmaceutical Control Bureau, Jalan Univetry of Health, Petaling Jaya, Malaysia; International Pharmaceutical Sections: Industrial Pharmacy, Laboratories and Medicines Control Setary Pharmacy and Community Pharmacy, Netherlands; WHO Collabotre for Drug Quality Assurance, Pharmaceutical Laboratory, Centre foScience, Health Sciences Authority, Singapore; WHO Collaboratifor Quality Assurance of Drugs, Potchefstroom University for ChristEducation, Potchefstroom, South Africa; WHO Collaborating Centre foReference Substances, National Corporation of Swedish Pharmacie

Laboratory, Kungens Kurva, Sweden; WHO Collaborating Centre ftional Infrared Reference Spectra, Swiss Federal Institute of TechnoloSwitzerland; WHO Roll Back Malaria Initiative, Geneva, Switzerland; WHProgramme for Research and Training in Tropical Diseases, Geneva, SWHO Stop TB Department, Geneva, Switzerland; WHO CollaboratingQuality Assurance of Essential Drugs, Department of Medical SciencesPublic Health, Nonthaburi, Thailand.

7/29/2019 WHO TRS 917, 2004 - 38th Report


Toxicology, University of Nigeria, Nsukka, Nigeria; Mr A.H. Al-AbdullahPublic Health, Doha, Qatar; Dr A. Al Na’amani, Supreme Board of Medical Appliances, Ministry of Public Health, Sana’a, Yemen; Dr MDirector, Pharmacy and Drug Control Department, Ministry of PubDoha, Qatar; Dr S.L. Ali, Zentrallaboratorium Deutscher Apotheker, Germany; Dr R. Allman, Medicines and Medical Devices Safety AuthoritUnit of the Ministry of Health, Auckland, New Zealand; Dr O.Medicopharmaceutical Humanitarian Centre, Clermont-Ferrand, FranArgenti, National Administration of Medicaments, Food and Medical TBuenos Aires, Argentina; Dr A. Artiges, European Directorate for theMedicines, Council of Europe, Strasbourg, France; Professor F. BallereHospitalier Universitaire de Nantes, France; Ms A.C. Baron, EuropeanIndustry Council/Active Pharmaceutical Ingredients Committee, CEGroup, Brussels, Belgium; Dr C. Barnstein, Drug Information Division UnPharmacopeia, Rockville, MD, USA; Dr P.M. Bazerque, Secretariat fand Health Regulation, Ministry of Health, Argentina; Professor Y. Mohammed V University, Laboratory of Galenical Pharmacy, Rabat, MD. Bentley, Senior Medicines Inspector, Medicines Control Agency, Yor

Mr G.H. Besson, Pharmaceutical Inspection Convention, Geneva, SDr S.M. Binti Jaafar, Pharmaceutical Services, Ministry of Health, BBegawan, Brunei Darussalam; Dr Peter Bläuenstein, Paul ScherreVilligen PSI, Switzerland; Professor H. Blume, Oberursel, Germany; Dr DFood and Drug Administration, Rockville, MD, USA; Dr L. Borka, Oslo, S. Botella, European Directorate for the Quality of Medicines, Council Strasbourg, France; Mr B. Botwe, Food and Drugs Board, Accra, GhBourdeau, ReMed Association, Mereville, France; Dr R. Boudet-DalbinPharmaceutical and Biological Sciences of Paris-Luxembourg, René University, Paris, France; Ms K. Bremer, Norwegian Medicines Contr

Oslo, Norway; Dr P.O. Bremer, Isopharma AS, Kjeller, Norway; Mr European Directorate for the Quality of Medicines, Council of Europe, SFrance; Mr G. Catto, World Federation of Proprietary Medicine ManLondon, England; Dr B. Chapart, Pharma Review Manager, GlobalDevelopment, Aventis Pharma, Anthony, France; Mrs Chen Yan, Certification, State Drug Administration, Beijing, People’s Republic of CChristen, Analytical Pharmaceutical Chemistry Laboratory, University Geneva, Switzerland; Dr W.-K. Chui, Department of Pharmacy, Nationaof Singapore, Singapore; Miss M. Cone, PJB Publications Ltd, RichmondDr J. Cordoba, Faculty of Pharmacy, University of Costa Rica, San JRica; Ms E.M. Cortes Montejano, Ministry of Health and Consumer Affair

tion for Drugs, Madrid, Spain; Dr P. Cox, Consultant in Nuclear MeRadiopharmacy, Bexhill on Sea, East Sussex, England; Ms F. DansereProducts and Food Branch Inspectorate, National Coordination CentOntario, Canada; Mr M.N. Dauramanzi, Medicines Control Authority of Harare, Zimbabwe; Professor H. de Jong, International PharmaceuticaCouncil, Courbevoie, France; Professor T. Dekker, Research Institutetrial Pharmacy, Potchefstroom University, Potchefstroom, South Afr

7/29/2019 WHO TRS 917, 2004 - 38th Report


Belgium; Dr A. Farina, Higher Institute of Health, Ministry of Health, RomE. Fefer, International Affairs, United States Pharmacopeia, Rockville,Mrs S. Fuerst, The United States Adopted Names Council ProgramMedical Association, Chicago, IL, USA; Dr H. Fukuda, Society of Japamacopoeia, Tokyo, Japan; Ms D. Gal, International Pharmaceutical The Hague, Netherlands; Mr S. Ghani, Division of Pharmaceutical Quapeutic Products Programme, Ottawa, Ontario, Canada; Ms E. GomQuality Assurance and Regulatory Affairs, Baxter Laboratories, Cali, Dr R. Gooch, Representative of the International Pharmaceutical Netherlands; Dr. T. Gosdschan, Intercantonal Office for the Control of Division of Inspections, Berne, Switzerland; Mr P. Graaff, WHO Regionathe Eastern Mediterranean, Alexandria, Egypt; Dr O. Gross, Pharmaceing Materials Unit, Directorate of Inspection of Establishments, French Health Safety of Health Products, Saint-Denis, France; Professor A.ADepartment of Biochemistry, College of Pharmacy, University of TaEgypt; Dr S. Haghighi, Pharmaceutical and Microbiology DepartmenPasteur of Iran, Teheran, Islamic Republic of Iran; Ms N. Haji Naim, PharServices, Ministry of Health, Jalan University, Petaling Jaya, Malays

Hartman, The Ottawa Hospital, Division of Nuclear Medicine, OttawCanada; Mr Y. Hayashi, Evaluation and Licensing Division, PharmaceMedical Safety Bureau, Ministry of Health, Labour and Welfare, TokyoP. Helboe, Pharmaceutical Affairs, Danish Medicines Agency, BrønshøjDr E. Henriksen, Division of Manufacturing and Product Quality, Officeance, US Food and Drug Administration, Rockville, MD, USA; Mr H. Intercantonal Office for the Control of Medicines, Berne, SwitzerlandJ. Hoogmartens, Catholic University of Leuven, Leuven, Belgium; DrAgency for Work, Health and Social Office for Health, Health DHamburg, Germany; Dr M.J. How, MJH International Ltd, Holbeto

England; Dr H. Ibrahim, DebioPharm SA, Lausanne, Switzerland; Dr J.Heikkilä, Council for International Organizations of Medical Sciences, Wcil of Churches, Geneva, Switzerland; Dr K.E. Iddir, Direction de la PharmMédicament, Tunis, Tunisia; Professor R. Jachowicz, Department of Phcal Technology and Biopharmaceutics, Jagiellonian University, CracoDr P. Jacqmain, Inspection Generale de la Pharmacie, Service PubliquSanté publiques, Securité de la Chaine alimentaire et EnvironnementBelgium; Mr M. Jahnsson, Technical Coordination Unit–InspectionsAgency for the Evaluation of Medicinal Products, London, England; PrShaohong, National Institute for the Control of Pharmaceutical andProducts, Ministry of Public Health, Beijing, People’s Republic of Chi

Jiragobchaipong, Bureau of Drug and Narcotic, Department of MedicaMinistry of Public Health, Nonthaburi, Thailand; Dr K.V. Jogi, Central DruLaboratories, ESIS Hospital, Thane, India; Dr A. Kakwemeire, National DControl Laboratory, Uganda National Drug Authority, Kampala, UgaKawamura, Japan Parenteral Drug Association, Tokyo, Japan; Mr Intercantonal Office for the Control of Medicines, Division of InspectioSwitzerland; Dr S. Kennedy, Technical Co-ordination, Inspection Sector

7/29/2019 WHO TRS 917, 2004 - 38th Report


Switzerland; Professor H.G. Kristensen, Royal Danish School of Pharmament of Pharmaceutics, Copenhagen, Denmark; Dr P.B. Kulkarni,Services Division, Bhabha Atomic Research Centre, Mumbai, India; MrDrugs Controller General, Directorate General of Health and Services,Health and Family Welfare, New Delhi, India; Mr R. Kuwana, MedicinAuthority, Harare, Zimbabwe; Mr J. Lanet, Qualassur, Paris, France; DMoustapha, National Drug Quality Control and Valuation LaboratoryCameroon; Mr H. Leblanc, Chairman, Active Pharmaceutical Ingredientee, Brussels, Belgium; Mr P. Lefévre, Medicines Agency, Saint Denis, E. Leinonen, National Agency for Medicines, Helsinki, Finland; Dr A.CHealth Protection Groups, Ministry of Health, Bogotá, Colombia; DNational Pharmaceutical Administration, Ministry of Health, Merah, Professor J. Lipták, Ministry of Health, Budapest, Hungary; Mr J. LismaThe Hague, Netherlands; Ms Low Min Yong, Pharmaceutical LaboratoryAnalytical Science, WHO Collaborating Centre for Drug Quality AssuranScience Authority, Singapore; Dr M.K. Majumdar, Damason ConsultancJadavpur, India; Dr F. Malik, National Institute of Health, Islamabad, PB. Mandal, WHO Collaborating Centre for Quality Assurance of Essen

Calcutta, India; Professor A.P. Mazurek, Drug Institute, Warsaw, PolMechkovski, Moscow, Russian Federation; Ms R. Mikolajczak, DepChemical Analysis, Radioisotope Centre, Polatom, Otwock Swielk PoMilek, International Pharmaceutical Excipients Council Europe, Good Practice Committee, Stuttgart, Germany; Ms M. Miljkovic, Institute of PhSerbia, Belgrade, Yugoslavia; Dr J.H. McB. Miller, European DirectorQuality of Medicines, Council of Europe, Strasbourg, France; PrMircheva, AESGP (Representative of WSMI), Brussels, Belgium; Dr A. MD Chemicals, Harrow, England; Dr A. Mitrevej, Vice-President for Acfairs, Pharmaceutical Association of Thailand, Bangkok, Thailand; Mr M

Inspectorate for Health Care, Rijswijk, Netherlands; Dr A. Mohd Moosa, General of Pharmaceutical Affairs and Drugs Control, Ministry of HealOman; Professor H. Möller, Central Laboratory of German PharmacistsGermany; Dr J. Molzon, Associate Director of International Programs,Drug Evaluation and Research, US Food and Drug Administration, RocUSA; Mrs A.B. Moraes da Silva, National School of Public Health (Coordination of Technical Cooperation, Rio de Janeiro, Brazil; Dr O. Mlatory and Scientific Affairs, International Federation of Pharmaceuticaturers Associations, Geneva, Switzerland; Dr G. Munro, Head of InspEnforcement, Medicines Control Agency, London, England; Dr S. Myapartment of Health, Food and Drug Administration, Ministry of Healt

Myanmar; Dr Myint-Sein, Myanmar Pharmaceutical Industries, Ministry Yangon, Myanmar; Dr D.V.S. Narasimhan, Division of Physical andSciences, International Atomic Energy Agency, Vienna, Austria; DrMahwah, NY, USA; Dr E. Njau, Arusha, United Republic of Tanzania; DrEuropean Agency for the Evaluation of Medicinal Products, London, EO.P.D. Noronha, N Dutta Marg, Andheri West, Mumbai, India; ProfOlaniyi, Department of Pharmaceutical Chemistry, College of Medicine

7/29/2019 WHO TRS 917, 2004 - 38th Report


of Korea; Dr I.J. Petersen, Department of Pharmaceutical Affairs, Ministand Social Security, Reykjavík, Iceland; Dr L.E. Pino Arango, MinistryBogotá, Colombia; Dr J. Pogány, Consivers Consulting and TranslatBudapest, Hungary; Dr W. Pohler, Pharmaceutical Sciences, AventFrankfurt am Main, Germany; Miss A. Poompanich, Bureau of Drug anDepartment of Medical Sciences, Ministry of Public Health, NonthaburMs M.-L. Rabouhans, Chiswick, England; Dr P. Rafidison, Internationceutical Excipients Council-Europe, Good Manufacturing Practices/Gbution Practice Committee, Global Life Sciences, Dow Corning, OpDr F. Rakiás, Head, Radioisotope Department, National Institute of Budapest, Hungary; Dr N. Ramamoorthy, Board of Radiation and Isotopogy, Department of Atomic Energy, Mumbai, India; Dr J. Reden, SciRegulatory Affairs, European Federation of Pharmaceutical Industriesciations, Brussels, Belgium; Mr G. Requin, Ministry of Health and QuaPort Louis, Mauritius; Mr P. Romagnoli, European Generic Medicines AAschimfarma, Milan, Italy; Dr D. Rumel, Brazilian Health SurveillancBrasilia, Brazil; Dr B. Sabri, Health Systems and Community Developmof WHO Representative, Riyadh, Saudi Arabia; M.S.C. Sanchez Gonza

for State Control of Drug Quality, Havana, Cuba; Dr Sang Gouwei, Natiofor the Control of Pharmaceutical and Biological Products, BeijingRepublic of China; Dr J.-M. Sapin, Head, Inspection Unit, AFSSA, LyoDr K. Satiadarma, Jl. Cipaganti 172, Bandung, Indonesia; Dr M. ScIntercantonal Office for the Control of Medicines, Control of ManufactSwitzerland; Professor J. Schlebusch, Medicines Control Council, DepHealth, Pretoria, South Africa; Ms M. Schmid, Saconnex d’Arve, SwitzerScholten, Coordinator, ICCTA Task Force on Pharmaceuticals and QuaMaterials, Germany; Dr H. Schrader, Physikalisch-Technisch BunBraunschweig, Germany; Dr J. Schrank, Scientific, Technical and Regfairs, Interpharma, Basel, Switzerland; Mr G. Schwartzman, Sarasota, FN. Sharif, Ministry of Health, Petaling Jaya, Sengalor, Malaysia; Dr G.V. SMinistry of Health, Moscow, Russian Federation; Dr S. Shaw, Internationceutical Federation, Netherlands; Dr A. Sheak, Department of Drug AdmMinistry of Health, Kathmandu, Nepal; Dr M. Sheikh, A/DHS, Syrian ArabDr E.B. Sheinin, Information and Standards Development, United Statecopeia, Rockville, MD, USA; Dr M. Siewert, Environmental Health aAventis Pharma, Frankfurt am Main, Germany; Dr S. Singh, Department ceutical Analysis, Nagar, Punjab, India; Ms K. Sinivuo, National Agenccines, Helsinki, Finland; Dr A.E. Smedstad, Norwegian Association ofPharmacists, Oslo, Norway; Dr M. Sm íd, State Institute for Drug Contr

Czech Republic; Dr R.J. Smith, Therapeutic Goods Administration LaWoden, Australian Capital Territory, Australia; Ms J. Solano Galvis, Health, Directorate-General for Public Health, Bogotá, Colombia; Dr J.-European Directorate for the Quality of Medicine, Council of Europe, SFrance; Mrs L. Stefanini-Oresíc, Croatian Institute for Medicine ContrCroatia; Dr A. Sulistiowati, Division of Therapeutic Products and Substances, National Quality Control Laboratory of Drugs and Foo

7/29/2019 WHO TRS 917, 2004 - 38th Report


Bureau of Food and Drugs, Alabang, Muntinlupa, Philippines; ProfessoDirectorate of Pharmacy and Medicines, Ministry of Public Health, BabTunisia; Ms M. Treebamroong, Quality Control Coordinator, for the Bureau of Drug and Narcotic, Department of Medical Sciences, MinistrNonthaburi, Thailand; Mr R. Tribe, Conformity Assessment Branch, TGoods Administration, Woden, Australian Capital Territory, Australia; MrBritish Pharmacopoeia Commission, London, England; Professor Tu Gsion of Pharmaceutical Chemistry, National Institute for the Control of Ptical and Biological Products, Ministry of Public Health, Beijing, Peopleof China; Dr J. Turner, Policy and Standards Inspection and EnforcemeDepartment of Health, Medicines Control Agency, London, England; DGlaxo Smith Kline, Ware, England; Ms E. Uramis Diaz, National Centre cal Products, Havana, Cuba; Mr S. Uzu, Planning Division, PharmaceuBureau, Ministry of Health and Welfare, Tokyo, Japan; Dr J.G. ValentStates Pharmacopeia, Rockville, MD, USA; Mr P. van der Hoeven, Activceutical Ingredients Committee, European Chemical Industry CounciBelgium; Dr J. van Oudtshoorn-Eckard, Monument Park, South AfVasanavathana, Office of Food and Drug Administration, Ministry of Pu

Nonthaburi, Thailand; Ms M. Veek, Associate Director for CommunicFood and Drug Administration, Rockville, MD, USA; Dr M. VenkateswaDrugs Standard Control Organization, Mumbai, India; Dr H. Vera Ruiz, InAtomic Energy Agency, Vienna, Austria; Dr J.-Y. Videau, Humanitariaand Pharmaceutical Centre, Clermont-Ferrand, France; Mr P.H. Vree, Ttorate of Health Care, Maasdam, Netherlands; Mr Wang Ping, PharCommission of the People’s Republic of China, Ministry of Health, BeijinRepublic of China; Dr J. Whitwell, Australian Nuclear Science and TOrganization, Australia; Dr S. Wibulpolprasert, Bureau of Health Policyning, Ministry of Public Health, Nonthaburi, Thailand; Mr L. Wiebe, UAlberta, Edmonton, Canada; Dr W. Wieniawski, Polish PharmaceuticWarsaw, Poland; Dr R.L. Williams, United States Pharmacopeia, RocUSA; Dr Woo Soo On, WHO Collaborating Centre for Drug Quality AHealth Sciences Authority, Singapore; Mr Yang Lahu, National InstitControl of Pharmaceutical and Biological Products, Ministry of PubBeijing, People’s Republic of China; Professor Yang Zhong-Yuan, GMunicipal Institute for Drug Control, Guangzhou, People’s Republic oZhou Haijun, National Institute for the Control of Pharmaceutical andProducts, WHO Collaborating Centre for Drug Quality Assurance, BeijinRepublic of China; Mr Zhu Dan, Shen Zhen, People’s Republic of ChZima, State Institute for Drug Control, Prague, Czech Republic; Profes

Ludwig Boltzmann-Institute for Nuclear Medicine, Institute for Biomedicogy and Physics, Vienna, Austria

References

7/29/2019 WHO TRS 917, 2004 - 38th Report


for Pharmaceutical Preparations. Thirty- fi fth report . Geneva, World H

Organization, 1999 (WHO Technical Report Series, No. 855) Annex

4. WHO Expert Committee on Speci fi cations for Pharmaceutical Prepa

Thirty-fourth report . Geneva, World Health Organization, 1996 (WHO

Technical Report Series, No. 863).


Thirty-seventh report . Geneva, World Health Organization, 2003 (WTechnical Report Series, No. 908) Annex 8.

7/29/2019 WHO TRS 917, 2004 - 38th Report


© World Health Organization

WHO Technical Report Series, No. 917, 2003

Annex 1Lists of available International Chemical Refer

Substances and International Infrared ReferenSpectra

1. International Chemical Reference Substan

International Chemical Reference Substances (ICRS) are esupon the advice of the WHO Expert Committee on SpecificPharmaceutical Preparations. They are supplied primarily f

physical and chemical tests and assays described in the specfor quality control of drugs published in The International Ph

poeia or proposed in draft monographs. The International Reference Substances are mainly intended to be used asstandards to calibrate secondary standards.

Directions for use and the analytical data required for the tefied in The International Pharmacopoeia are given in the ceenclosed with the substances when distributed.

International Chemical Reference Substances may also in tests and assays not described in The International Ph

poeia. However, the responsibility for assessing the suitabilsubstances then rests with the user or with the pharmcommission or other authority that has prescribed the usesubstances.

It is generally recommended that the substances should b

protected from light and moisture and preferably at a tempeabout +5°C. When special storage conditions are requirestated on the label or in the certificate. It is recommendeduser purchase only an amount sufficient for immediate use.

The stability of the International Chemical Reference Sukept at the Collaborating Centre is monitored by reg

7/29/2019 WHO TRS 917, 2004 - 38th Report


Table 1

Available International Chemical Reference Substances

Catalogue Reference substance Package

number size

9930375 p -acetamidobenzalazine 25mg

9930202 acetazolamide 100mg

9930204 allopurinol 100mg 9930206 amidotrizoic acid 100mg

9930191 2-amino-5-nitrothiazole 25mg

9930194 3-aminopyrazole-4-carboxamide hemisulfate 100mg

9930193 3-amino-2,4,6-triiodobenzoic acid 100mg

9930208 amitriptyline hydrochloride 100 mg

9930209 amodiaquine hydrochloride 200 mg

9930210 amphotericin B 400mg

9930211 ampicillin (anhydrous) 200mg

9930212 ampicillin sodium 200mg

9930213 ampicillin trihydrate 200mg

9930214 anhydrotetracycline hydrochloride 25mg

9930215 atropine sulfate 100mg

9930216 azathioprine 100mg

9930218 bacitracin zinc 200mg

9930219 beclometasone dipropionate 200 mg

9930220 bendazol hydrochloride 100mg

9930223 benzobarbital 100mg

9930224 benzylamine sulfate 100mg 9930225 benzylpenicillin potassium 200 mg

9930226 benzylpenicillin sodium 200mg

9930227 bephenium hydroxynaphthoate 100 mg

9930228 betamethasone 100mg

9930229 betamethasone sodium phosphate 100mg

9930230 betamethasone valerate 100mg

9930231 betanidine sulfate 100mg

9930233 bupivacaine hydrochloride 100 mg

9930234 caffeine 100mg

9930236 calcium folinate (leucovorin calcium) 100mg

9930237 captopril 100mg

9930238 captopril disulfide 25mg

9930239 carbamazepine 100mg

9930240 carbenicillin monosodium 200mg

9930241 chloramphenicol 200mg

7/29/2019 WHO TRS 917, 2004 - 38th Report


Table 1 (continued)


number size

9930256 ciprofloxacin hydrochloride 400mg

9930252 ciprofloxacin by-compound A 20mg

9930253 ciprofloxacin desfluoro-compound 20mg

9930254 ciprofloxacin ethylenediamine-compound 20mg 9930255 ciprofloxacin fluoroquinolonic acid 20mg

9930258 cisplatin 100mg

9930259 clomifene citrate 100mg

clomifene citrate Z -isomer see zuclomifene

9930261 cloxacillin sodium 200mg

9930262 colecalciferol (vitamin D3) 500mg

9930263 cortisone acetate 100mg

9930265 dapsone 100mg

9930266 desoxycortone acetate 100mg 9930267 dexamethasone 100mg

9930268 dexamethasone acetate 100mg

9930269 dexamethasone phosphoric acid 100 mg

9930270 dexamethasone sodium phosphate 100mg

9930281 diazepam 100mg

9930282 diazoxide 100mg

9930283 dicloxacillin sodium 200mg

9930284 dicolinium iodide 100mg

9930285 dicoumarol 100mg

9930287 diethylcarbamazine dihydrogen citrate 100mg

9930288 digitoxin 100mg

9930289 digoxin 100mg

9930290 dopamine hydrochloride 100mg

9930292 doxorubicin hydrochloride 100 mg

9930294 emetine hydrochloride 100mg

9930197 4-epianhydrotetracycline hydrochloride 25mg

9930198 4-epitetracycline hydrochloride 25 mg

9930295 ergocalciferol (vitamin D2) 500mg

9930296 ergometrine hydrogen maleate 50 mg

9930297 ergotamine tartrate 50mg

9930298 erythromycin 250mg

9930299 erythromycin B 150mg

9930300 erythromycin C 25mg

9930301 estradiol benzoate 100mg

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number size

9930311 fludrocortisone acetate 200mg

9930312 fluorouracil 100mg

9930313 fluphenazine decanoate dihydrochloride 100mg

9930314 fluphenazine enantate dihydrochloride 100mg

9930315 fluphenazine hydrochloride 100mg 9930316 folic acid 100mg

9930195 3-formylrifamycin 200mg

9930355 framycetin sulfate (neomycin B sulfate) 200mg

9930318 furosemide 100mg

9930319 gentamicin sulfate 100mg

9930322 griseofulvin 200mg

9930323 haloperidol 100mg

9930324 hydrochlorothiazide 100mg

9930325 hydrocortisone 100mg

9930326 hydrocortisone acetate 100mg

9930327 hydrocortisone sodium succinate 200 mg

9930188 (-)-3-(4-hydroxy-3-methoxyphenyl)-2-

hydrazino-2-methylalanine

(3-O -methylcarbidopa) 25mg

9930189 (-)-3-(4-hydroxy-3-methoxyphenyl)-

2-methylalanine

(3-O -methylmethyldopa) 25mg

9930328 ibuprofen 100mg

9930329 imipramine hydrochloride 100mg

9930330 indometacin 100mg

9930370 o -iodohippuric acid 100mg

9930331 isoniazid 100mg

9930332 kanamycin monosulfate 12mg

9930333 lanatoside C 100mg

9930334 levodopa 100mg

9930335 levonorgestrel 200mg

9930336 levothyroxine sodium 100mg

9930337 lidocaine 100mg

9930338 lidocaine hydrochloride 100mg

9930339 liothyronine sodium 50mg

9930340 loperamide hydrochloride 100mg

9930341 b d l 200

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Table 1 (continued)


number size

9930423 sulfapyridine (193°C) 4g

9930286 dicyanodiamide (210°C) 1g

9930411 saccharin (229°C) 1g

9930235 caffeine (237°C) 1g 9930382 phenolphthalein (263°C) 1g

9930343 metazide 100mg

9930344 methaqualone 100mg

9930345 methotrexate 100mg

9930346 methyldopa 100mg

9930347 methyltestosterone 100mg

9930348 meticillin sodium 200mg

9930350 metronidazole 100mg

9930351 nafcillin sodium 200mg 9930354 neamine hydrochloride

(neomycin A hydrochloride) 0.5 mg

neomycin B sulfate see framycetin sulfate

9930356 neostigmine metilsulfate 100mg

9930357 nicotinamide 100mg

9930358 nicotinic acid 100mg

9930359 nifurtimox 100mg

9930360 niridazole 200mg

9930361 niridazole-chlorethylcarboxamide 25 mg

9930366 norethisterone 100mg

9930367 norethisterone acetate 100mg

9930369 nystatin 200mg

9930371 ouabain 100mg

9930372 oxacillin sodium 200mg

9930373 oxytetracycline dihydrate 200mg

9930374 oxytetracycline hydrochloride 200 mg

9930376 papaverine hydrochloride 100mg

9930377 paracetamol 100mg 9930378 paromomycin sulfate 75mg

9930381 pheneticillin potassium 200mg

9930383 phenoxymethylpenicillin 200mg

9930384 phenoxymethylpenicillin calcium 200 mg

9930385 phenoxymethylpenicillin potassium 200mg

9930387 phenytoin 100mg

7/29/2019 WHO TRS 917, 2004 - 38th Report



number size

9930398 procaine hydrochloride 100mg

9930399 procarbazine hydrochloride 100 mg

9930400 progesterone 100mg

9930401 propicillin potassium 200mg

9930402 propranolol hydrochloride 100 mg 9930403 propylthiouracil 100mg

9930404 pyrantel embonate (pyrantel pamoate) 500mg

9930405 pyridostigmine bromide 100mg

9930406 reserpine 100mg

9930407 retinol acetate (solution) 5capsa

9930408 riboflavin 250mg

9930409 rifampicin 300mg

9930410 rifampicin quinone 200mg

9930412 sodium amidotrizoate 100mg

9930413 sodium cromoglicate 100mg

9930415 spectinomycin hydrochloride 200 mg

9930416 streptomycin sulfate 100mg

9930417 sulfacetamide 100mg

9930419 sulfamethoxazole 100mg

9930420 sulfamethoxypyridazine 100mg

9930421 sulfanilamide 100mg

9930424 sulfasalazine 100mg

9930425 tamoxifen citrate 100mg

9930426 tamoxifen citrate E -isomer 10mg

9930427 testosterone enantate 200mg

9930428 testosterone propionate 100mg

9930429 tetracycline hydrochloride 200 mg

9930430 thioacetazone 100mg

9930196 4,4¢-thiodianiline 50mg

thyroxine sodium see levothyroxine sodium

9930431 tolbutamide 100mg

9930432 tolnaftate 100mg 9930433 toluene-2-sulfonamide 100mg

9930434 trimethadione 200mg

9930435 trimethoprim 100mg

9930436 trimethylguanidine sulfate 100 mg

9930440 vincristine sulfate 9.7mg/vial

7/29/2019 WHO TRS 917, 2004 - 38th Report


amiloride hydrochlorideamitriptyline hydrochloampicillin trihydrate

beclometasone dipropionatebenzylpenicillin potassium

biperiden hydrochloridebupivacaine hydrochlor

WHO Collaborating Centre for Chemical Reference SubApoteket ABProduktion & LaboratorierCentrallaboratoriet, ACLPrismavägen 2SE-141 75 Kungens Kurva, Sweden

Fax: +46 8 740 60 40or e-mail: [email protected]

International Chemical Reference Substances are supplied ostandard packages indicated in the following list.

2. International Infrared Reference Spectra

The WHO Collaborating Centre for Chemical Reference Suis able to supply 69 International Infrared Reference Spect

Orders should be sent to:

WHO Collaborating Centre for Chemical Reference SubstaApoteket ABProduktion & LaboratorierCentrallaboratoriet, ACL

Prismavägen 2SE-141 75 Kungens Kurva, SwedenFax: +46 8 740 60 40or e-mail: [email protected]

The following International Infrared Reference Spectra are available from the Centre:

aceclidine salicylateacetazolamideallopurinol

7/29/2019 WHO TRS 917, 2004 - 38th Report


dexamethasonedexamethasone acetate,

monohydratedextromethorphan

hydrobromidediazepam

dicolinium iodidedicoumaroldiethylcarbamazine dihy

citratediphenoxylate hydrochl

erythromycin ethylsuccinateerythromycin stearateetacrynic acid

ethionamideethosuximide

furosemide

gallamine triethiodide glibenclamide

haloperidol hydrochlorothiazide

ibuprofenimipramine hydrochloride

indometacinisoniazid

lidocainelidocaine hydrochloride

lindane

metronidazole miconazole nitrate

niclosamide

nicotinamide

noscapine

oxamniquine

papaverine hydrochloridephenobarbitalphenoxymethylpenicillin calciumphenytoin

primaquine phosphatepropylthiouracilprotionamidepyrimethamine

salbutamol

salbutamol sulfatesulfadimidine

sulfadoxine

sulfamethoxazolesulfamethoxypyridazine

tiabendazoletrihexyphenidyl hydrochloride

trimethoprim

valproic acid verapamil hydrochloride

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Annex 2

Good trade and distribution practices forpharmaceutical starting materials

Introductory note

Scope

General considerations

Glossary

1. Quality management

2. Organization and personnel

3. Premises

4. Warehousing and storage

5. Equipment

6. Documentation

7. Repackaging and relabelling

8. Complaints

9. Recalls

10. Returned goods

11. Handling of non-conforming materials

12. Dispatch and transport

13. Contract activities

References

Introductory note

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ing, labelling, relabelling, storage, distribution and documand record-keeping practices.

WHO is concerned about the quality of materials used for tfacture of pharmaceutical products because the quality of maceutical starting materials can be affected by the lack of control of activities including packaging, repackaging, labelabelling, storage and distribution of the materials used inceutical products.

Packaging, repackaging, labelling, relabelling, storage andtion are the usual practices of a number of parties involvtrade and distribution of pharmaceutical starting materials, traders, brokers and distributors. Other activities include thof Certificates of Analysis. Improper trading practices (e.g

ing, storage and distribution) can pose a significant risk to thof pharmaceutical starting materials. Experience has showntivities such as repackaging and relabelling, in particular, canthe risk of contamination, cross-contamination, mix-ups, degand changes in physical properties.

To maintain the original quality, all activities such as packagiling and retesting of materials should be carried out accoGMP, good storage practice (GSP) and good trade and dispractice (GTDP).

This guideline is a stand-alone text. However, there some overlap with other guidelines such as those for GGSP.

Scope

These guidelines are applicable to all persons and companiesin handling pharmaceutical starting materials (i.e. active phtical ingredients (APIs) and excipients), including the matmoved during the process of pharmaceutical product manThe guidelines apply to all parties involved in trade and disb k li di ib d

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Persons and companies performing processing activities,mixing, micronization, relabelling or repackaging of pharmstarting materials, should also comply with all relevant aGMP.

In addition to this text, the good storage practices for pharma

are applicable.

General considerations

The objective of the implementation of these guidelines is tthe quality and integrity of the starting material and the phtical product.

The guidelines should be considered and implemented inte

suppliers, such as:

— pharmaceutical manufacturers, including manufacturersmediate and/or finished products;

— distributors;— manufacturers of pharmaceutical starting materials;— brokers; and— other suppliers.

They are also relevant to:

— governments;— regulatory bodies;— international organizations and donor agencies involve

curement tenders;— relevant trade organizations;— certifying bodies; and— all parties involved in trade and distribution.

Member States should take appropriate measures to enimplementation of these guidelines. The guidelines can be ustool in the prevention of the trade in counterfeit and sub

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The role of the producer, manufacturer, trader, broker or din sharing the responsibility for a quality product is evidemust ensure that materials are of the quality required for upharmaceutical industry, as each plays an important part in tfacture and supply chain to ensure that a quality product is suthe patient.

For this reason, materials can only be reclassified from ceutical grade to non-pharmaceutical grade and not frpharmaceutical grade to pharmaceutical grade.

Each batch of pharmaceutical starting material should nortested by its manufacturer for compliance with its specificatioresults are obtained from skip lot testing this should be indthe Certificate of Analysis issued by the manufacturer.

Glossary

The definitions given below apply to the terms as used in thelines. They may have different meanings in other contexts.

active pharmaceutical ingredient (API)

Any substance or mixture of substances intended to be usmanufacture of a pharmaceutical dosage form and that, whenbecomes an active ingredient of that pharmaceutical dosaSuch substances are intended to furnish pharmacological aother direct effect in the diagnosis, cure, mitigation, treatprevention of disease or to affect the structure and functibody.

agreement Arrangement undertaken by and legally binding on parties

batch (or lot)

A defined quantity of starting material, packaging material,t d in in l i f th

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batch number (or lot number)

A distinctive combination of numbers and/or letters which identifies a batch on the labels, the batch records, the certianalysis, etc.

calibration

The set of operations that establish, under specified condirelationship between values indicated by an instrument or smeasuring (especially weighing), recording, and controllinvalues represented by a material measure, and the correknown values of a reference standard. Limits for acceptanresults of measuring should be established.

certificate of analysis (COA)

A document listing the results of testing a representativdrawn from the batch to be delivered. A COA should be equthe WHO Model COA (1).

consignment

The quantity of a pharmaceutical starting material mademanufacturer and supplied at one time in response to a prequest or order. A consignment may comprise one or more or containers and may include material belonging to more

batch.

contract

Business agreement for supply of goods or performance of wspecified price.

Earliest expiry/first out principle concept (EEFO)

A distribution procedure to ensure that the stock with th

expiry date is distributed and/or utilized before an identical swith a later expiry date is distributed and/or utilized.

excipient

A substance or compound, other than the active pharmi di t d k i t i l th t i i t d d d

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First in/first out principle concept (FIFO)

A distribution procedure to ensure that the oldest stock is diand/or utilized before a newer and identical stock item is diand/or utilized.

good manufacturing practice (GMP)

That part of quality assurance which ensures that prodconsistently produced and controlled to the quality sappropriate to their intended use and as required by the mauthorization.

homogeneous material

Material of uniform consistency and composition throughou

in-process control

Checks performed during production in order to monitor aessary to adjust the process to ensure that the material confospecifications. The control of the environment or equipmentbe regarded as a part of in-process control.

intermediate

Partly processed material that must undergo further manusteps before it becomes a bulk product.

labelling

The action involving the selection of the correct label, required information, followed by line-clearance and apof the label.

manufacture

All operations of purchase of materials, production, qualityrelease, storage, and distribution of pharmaceutical starting mand the related controls.

original manufacturer

Person or company manufacturing a material to the stage ais designated as a pharmaceutical starting material.

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and repackaging, labelling and relabelling, to completiofinished pharmaceutical starting materials.

quality assurance

A wide-ranging concept covering all matters that individuallectively influence the quality of a product, including pharm

starting materials. It is the totality of the arrangements madeobject of ensuring that pharmaceutical starting materials andceutical products are of the quality required for their intend

quality control

All measures taken, including the setting of specifications, stesting and analytical clearance, to ensure that raw materiamediates, packaging materials and finished pharmaceuticamaterials conform to established specifications for identity, purity and other characteristics.

quarantine

The status of materials isolated physically or by other effectipending a decision on their subsequent approval or rejectio

recall

A process for withdrawing or removing a pharmaceutical

from the distribution chain because of defects in the macomplaints of a serious nature. The recall might be initiatemanufacturer/importer/distributor or a responsible agency.

relabelling

The process of putting a new label on the material (see also l

repackaging

The action of changing the packaging of the material.

retest date

The date when a material should be re-examined to ensurestill suitable for use.

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basis, with the understanding that those batches not tested meet all the acceptance criteria established for that prodrepresents a less than full schedule of testing and should tbe justified, presented to, and approved by, the regulatory before implementation. When tested, any failure of the staterial to meet the acceptance criteria established for the perio

lot) test should be handled by proper notification of the appregulatory authority (authorities). If these data demonstraterestore routine testing, then batch-by-batch release testing sreinstated.

supplier

Person or company providing pharmaceutical starting matrequest. Suppliers may be distributors, manufacturers, trad

validation

The documented act of proving that any procedure, procesment, material, activity, or system actually leads to the results.

1. Quality management

1.1 Within an organization, quality assurance serves as a ment tool. In contractual situations quality assurance also generate confidence in the supplier. There should be a docquality policy describing the overall intentions and directiosupplier regarding quality, as formally expressed and authomanagement.

1.2 Quality management should include:

— an appropriate infrastructure or “quality system”, encothe organizational structure, procedures, processes and r

— the systematic actions necessary to ensure adequate cthat a material (or service) and the relevant documentsatisfy given requirements for quality (The totality

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cific training and should be provided with the necessary pequipment.

2.6 Personnel who may be exposed to materials from open cshould maintain good hygiene, have no open woundsequipped with an appropriate protective outfit, such as glovand goggles.

3. Premises

3.1 Premises must be located, designed, constructed, adamaintained to suit the operations to be carried out. Their ladesign must aim to minimize the risk of errors and permitcleaning and maintenance in order to avoid cross-contamina

ups, build-up of dust or dirt and, in general, any adverse effequality of materials.

3.2 Measures should be in place to prevent unauthorizedfrom entering the premises.

3.3 Premises should be designed and equipped so as to affomum protection against the entry of insects, rodents or other

3.4 Suitable supporting facilities and utilities (such as airlighting and ventilation) should be in place and appropriaactivities performed.

3.5 There should normally be a separate sampling area forceutical starting materials in a controlled environment. If saperformed in the storage area, it should be conducted in suchto prevent contamination or cross-contamination. Adequateprocedures should be in place for the sampling areas.

4. Warehousing and storage

GSP is applicable in all circumstances in which and all are

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designed and equipped to allow containers of incoming mabe cleaned before storage if necessary.

4.4 Segregated areas should be provided for the storage ofrecalled and returned materials, including those with packaging.

4.5 Segregated areas and materials should be appridentified.

4.6 The required storage conditions as specified for theshould be maintained within acceptable limits. The storashould be kept clean and dry.

4.7 Where special storage conditions are required (e.g. prequirements for temperature or humidity) these should be

monitored and recorded.4.8 Highly active materials, narcotics, other dangerous dsubstances presenting special risks of abuse, fire or explosiobe stored in safe, dedicated and secure areas. In addition inteconventions and national legislation may apply.

4.9 Special attention should be given to the design, use, cleamaintenance of all equipment for bulk handling and storagetanks and silos.

4.10 Spillages should be cleaned as soon as possible to presible cross-contamination and hazard.

4.11 Provision should be made for the proper and safe swaste materials awaiting disposal. Toxic substances and flmaterials should be stored in suitably designed, separate, cltainers in enclosed areas, taking into account the relevantlegislation.

4.12 A system should be in place to ensure that those materiexpire first are sold or distributed first (earliest expiry(EEFO)). Where no expiry dates are specified for the matefirst in/first out (FIFO) principle should be applied.

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5. Equipment

5.1 Equipment must be located, designed, constructed, adapand maintained to suit the operations to be carried out. Dequipment should not be used, and should either be remlabelled as defective. Equipment should be disposed of in suas to prevent any misuse.

5.2 The layout, design and use of equipment must aim to the risk of errors and to permit effective cleaning and mainteavoid cross-contamination, build-up of dust or dirt and anyeffect on the quality of materials.

5.3 Fixed pipework should be clearly labelled to indicate theand, where applicable, the direction of flow.

5.4 All services, piping and devices should be adequately maspecial attention paid to the provision of non-interchangenections or adaptors for dangerous gases, liquids and other m

5.5 Balances and other measuring equipment of an appropriand precision should be available and should be calibrascheduled basis.

5.6 Procedures should be in place for the operation and maiof equipment. Lubricants and other materials used on surf

come into direct contact with the materials should be of the ate grade, e.g. food-grade oil.

5.7 Washing and cleaning equipment should be chosen and that it cannot be a source of contamination.

5.8 Dedicated equipment should be used where possible wdling and/or processing pharmaceutical starting materialnon-dedicated equipment is used, cleaning validation sh

performed.

6. Documentation

6.1 Documents, in particular instructions and procedures r

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6.3 Original Certificates of Analysis (COAs) should acmaterials supplied by manufacturers to suppliers. COAs ithe manufacturer should indicate which results were obttesting the original material and which results came fromtesting. The use of the Model COA as adopted by the WHOCommittee on Specifications for Pharmaceutical Prepar

recommended (1).6.4 Before any material is sold or distributed, the supplieensure that the COAs and results are available and that the rwithin the required specifications. Alternatively the custombe informed without delay of the results as soon as theseavailable. For each shipment the COA should be forwardpharmaceutical product manufacturer.

6.5 The original manufacturer and intermediaries handlingterial should always be traceable and the information avaauthorities and end-users, downstream and upstream.

6.6 Mechanisms should exist to allow for transfer of infincluding the transfer of quality or regulatory information bmanufacturer and a customer, and of information to the rauthority upon request.

6.7 Labels applied to containers should be clear, unambigu

manently fixed and in the company’s agreed format. The infon the label should be indelible.

6.8 Each container should be identified by labelling bearinthe following information:

— the name of the pharmaceutical starting material, includand reference to pharmacopoeias, where relevant;

— if applicable, the International Nonproprietary Names (

— the amount (weight or volume);— the batch number assigned by the original manufactur

batch number assigned by the repacker, if the material repacked and relabelled;

— the retest date or expiry date (where applicable);

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7. Repackaging and relabelling

7.1 Operations, such as combining into a homogeneous bpackaging and/or relabelling, are manufacturing processes performance should therefore follow GMP.

7.2 Special attention should be given to the following poin— prevention of contamination, cross-contamination and m— security of stocks of labels, line clearance checks, on-lin

tions, destruction of excess batch-printed labels;— good sanitation and hygiene practices;— maintaining batch integrity (normally mixing of differen

of the same solid material should not be done);— as part of batch records, all labels that were removed

original container during operations, and a sample oflabel, should be kept;

— if more than one batch of labels is used in one operationof each batch should be kept; and

— maintaining product identity and integrity.

7.3 When different batches of a material from the samemanufacturing site are received by a distributor and c

into a homogeneous batch, the conformity of each batchspecification should be confirmed before it is added.

7.4 Only materials from the same manufacturing site recedistributor and conforming to the same specifications can bIf different batches of the same material are mixed to formgeneous batch it should be defined as a new batch, tested andwith a batch certificate of analysis. In such cases the custom

be informed that the material supplied is a mixture of manubatches. The supplied material must have a certificate of coto a specification at date of supply.

7.5 In all cases the original COA of the original manufacturbe provided If retesting is done both the original and the n

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7.7 The re-use of containers should be discouraged unless tbeen cleaned using a validated procedure. Recycled cshould not be used unless there is evidence that the qualimaterial packed will not be adversely affected.

7.8 Materials should be repackaged only if efficient envircontrol exists to ensure that there is no possibility of contamcross-contamination, degradation, physicochemical changemix-ups. The quality of air supplied to the area should be suthe activities performed, e.g. efficient filtration.

7.9 Suitable procedures should be followed to ensure procontrol.

7.10 Containers of repackaged material and relabelled c

should bear both the name of the original manufacturing sitname of the distributor/repacker.

7.11 Procedures should be in place to ensure maintenanidentity and quality of the material by appropriate means, boand after repackaging operations.

7.12 Batch release procedures should be in place in accordGMP.

7.13 Only official pharmacopoeial methods or validated test methods should be used for the analysis.

7.14 Samples of APIs and excipients of appropriate quantitibe kept for at least 1 year after the expiry or retest date, or fafter distribution is complete.

7.15 The repacker and relabeller should ensure that the st

the material is not adversely affected by the repackaging oling. Stability studies to justify the expiry or retest datesshould be conducted if the pharmaceutical starting material iaged in a container different from that used by the original turer. It is recognized that some excipients may not need at bilit t di

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8.2 Any complaint concerning a material defect should be and thoroughly investigated to identify the origin or reasocomplaint (e.g. the repackaging procedure, the original maing process, etc.).

8.3 If a defect in a pharmaceutical starting material is discosuspected, consideration should be given as to whether otheshould be checked.

8.4 Where necessary, appropriate follow-up action, possibing a recall, should be taken after investigation and evaluaticomplaint.

8.5 The manufacturer and customers should be informed ifneeded following possible faulty manufacturing, packaging

ration, or any other serious quality problems with a pharmstarting material.

9. Recalls

9.1 There should be a system for recalling promptly and efrom the market, materials known or suspected to be defec

9.2 The original manufacturer should be informed in the erecall.

9.3 There should be established written procedures for the tion of any recall activity; these should be regularly cheupdated.

9.4 All recalled materials should be stored in a secure, se

area while their fate is decided.

9.5 In the event of serious or potentially life-threatening situcustomers and competent authorities in all countries to whicmaterial may have been distributed should be promptly inf

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10. Returned goods

10.1 Goods returned to the supplier should be appridentified and handled in accordance with a procedure addrleast the keeping of the material in quarantine in a dedicaand its assessment and disposition by a designated person. Wdoubt arises over the quality of the materials, they shoul

considered suitable for reissue or reuse.

11. Handling of non-conforming materials

11.1 Non-conforming materials should be handled in acwith a procedure that will prevent their introduction orduction into the market. Records covering all activities,

destruction, disposal, return and reclassification, shmaintained.

11.2 An investigation should be performed to establish whother batches are also affected. Corrective measures shouldwhere necessary.

11.3 The disposition of the material, including downgradingsuitable purposes should be documented.

11.4 Non-conforming materials should never be blended terials that do comply with specifications.

12. Dispatch and transport

12.1 Materials should be transported in a manner that will emaintenance of controlled conditions where applicable (e.g.

ture, protection from the environment). The transport procenot adversely affect the materials.

12.2 Requirements for special transport and/or storaditions should be stated on the label. If the pharmaceutica

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12.4 Procedures should be in place to ensure proper cleaprevention of cross-contamination when liquids (tanks) anpacked materials are transported.

12.5 The bulk transport of pharmaceutical starting matquires numerous precautions to avoid contamination an

contamination. The best practice is to use dedicated eqtanks or containers.

12.6 Packaging materials and transportation containers ssuitable to prevent damage to the pharmaceutical starting during transport.

12.7 For bulk transport, validated cleaning procedures sused between loadings, and a list of restricted previous carg

be supplied to the transport companies.

12.8 Steps should be taken to prevent unauthorized accematerials being transported.

12.9 General international requirements regarding safety(e.g. prevention of explosion and of contamination of thement, etc.) should be observed.

13. Contract activities

13.1 Any activity performed, as referenced in the GMP anguidelines, delegated to another party, should be agreed uwritten contract.

13.2 The contract giver should evaluate the proposed

acceptor’s compliance with GTDP before entering into an ag

13.3 All contract acceptors should comply with the requirethese guidelines. Special consideration should be given to thtion of cross-contamination and to maintaining traceability

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References


Thirty-sixth Report. Geneva, World Health Organization, 2002 (WHO

Technical Report Series, No. 902).


Thirty-seventh Report . World Health Organization, Geneva, 2003 (T

Report Series, No. 908).

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Annex 3WHO pharmaceutical starting materials certifi

scheme (SMACS): guidelines on implementati

Preamble

The quality of pharmaceuticals has been a concern of WHits inception. Owing to the nature of these products, thisincludes the quality of the starting materials, i.e. active pharcal ingredients (APIs) and excipients, used for the prod

pharmaceuticals.This guidance text, in combination with other recommendaguidelines issued by WHO, will be an important step towaring the quality and traceability of pharmaceutical starting and in assigning the responsibility for specifications withincesses of manufacture, storage and distribution of pharmstarting materials.

Member States are urged to establish and maintain a legal frand regulatory approach to ensure that good practices for and distribution of pharmaceutical starting materials are Member States can establish appropriate regulatory control menting one or both of the following approaches:

— licensing of suppliers, including traders, brokers and disand/or

— a registration or notification system of suppliers, includinbrokers and distributors.

A variety of WHO guidelines ready for use and inclunational legislation are available. Their implementation wicial throughout the process towards ensuring the availability

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The use of the new certification scheme is based on the existquality assurance system for the production of starting mat

All parties involved in the trade and distribution of pharmstarting materials are strongly encouraged to comply with thManufacturers of pharmaceutical products should encouassist their suppliers to use good storage practice (GSP), G

the relevant parts of good manufacturing practice (GMP).

Trade associations are also encouraged to incorporate thciples into their own codes of practice to be followed members.

Another recommendation is the development of a global listing information on suppliers (e.g. names and addresses) customers to verify supplier information. A global databa

later be established to assist in the attempt to address the prcounterfeiting of pharmaceutical materials.

Training workshops and conferences on GTDP should be ppromote these principles.

The establishment of model certificates for GSP and GTDP envisaged.

National legislation should ensure that penalties can be

when persons or suppliers are found to be in violation of le

An alert system should be established by the competent autprevent trade in non-conforming materials that could put prisk. WHO should be informed of such instances so that thistion can be made available to other national or regional aufor action as necessary.

Ultimate goal

Close collaboration of all partners throughout the distributrade chain should be established and maintained to protecthealth.

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identified. The Expert Committee was informed of the recotions of a consultation on “Starting materials for pharmproducts: control and safe trade”, held in Geneva in May 199as of the report from this consultation which is available inChinese, English, French, Spanish and Russian. The repoavailable on the Internet at http://www.who.int/medici

startmats.html.The Committee also noted that the World Health Assemadopted the proposed resolution on the Revised Drug (WHA52.19) in May 1999, and was informed of a press rele22 May 1999 regarding the above-mentioned World Health Aresolution. The resolution requested WHO to prepare a newfor the certification of starting materials moving in internatiomerce. It was agreed at the thirty-eighth meeting of the Exp

mittee that an increased awareness of existing guidelines spromoted. The Committee noted that several recommendabeen made in the report of the consultation of May 1998 for governments, manufacturers, traders and brokers as well as bThe Organization would need to collaborate with all the pvolved. It was suggested that the above-mentioned recommeshould be consolidated and priorities assigned, and the document distributed widely to relevant associations and re

tive bodies.

On the basis of the above considerations, a new WHO SchemCertification of Pharmaceutical Starting Materials Moving intional Commerce is being proposed. The document outliningscheme was drafted at an informal consultation before beilated for comments and rediscussed during a consultationAugust 2001. Further rounds of consultation took place including a meeting held in July of that year. The text was raccordance with the comments received.

There is currently insufficient legislative control over the maand distribution of pharmaceutical starting materials in maMember States. It is, however, recognized that in some

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commerce”. It should be noted, however, that the concepproposed scheme and its application differ in certain aspectsscheme for pharmaceutical products, namely, in the provisifor alternative quality assurance systems and self-assessmemanufacturers of pharmaceutical starting materials. The laalso be linked to an inspection by a national authority other

one in the country of manufacture.It is further suggested to consider the use of the “Model ceranalysis for active pharmaceutical ingredients, excipients acinal products (COA)” that would serve in the trade ofmaterials and for manufacturers of pharmaceutical suexcipients and medicinal products, as recommended by rWHA52.19 (Annex 2 of reference (1)) together with the “Cations for requesting analysis of drug samples” (Annex 3 of

(1)) to complement this scheme.

The newly proposed scheme consists of:

1. A Model Certificate for Manufacture of PharmaceuticaMaterials issued by the competent national authority,

or, alternatively:

2. A Model Certificate for Manufacture of Pharmaceutica

Materials issued by the manufacturer.

Scope

The scheme described in this document is intended for pharcal starting materials, obtained through chemical synthesis. Bblood derivatives are beyond the scope of this scheme.

It is envisaged to evaluate this scheme describing a new glob

nism for its applicability and use after a certain length of tim

Contents

1. Provisions and objectives

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Appendix 2

Model Certificate for Manufacture of Pharmaceutical Starting Materialsissued by the manufacturer

Appendix 3

Glossary and key words

1.Provisions and objectives1.1 A comprehensive system of quality assurance should be founded on a reliable system of licensing and analysis omaterials, as well as upon assurance, obtained through indinspection, that all manufacturing operations are carried ouformity with accepted norms referred to as good manufacturtices (GMP). Production and quality control should be indof one another.

1.2 The World Health Assembly endorsed the requirementspractices in the manufacture and quality control of drugs ( 2) to henceforth as “GMP as recommended by WHO”). The Gincludes good manufacturing practices for pharmaceuticamaterials (active pharmaceutical ingredients and pharmexcipients).

1.3 The Scheme is an administrative instrument that can be

1.3.1 A Member State to attest that:

— a specific starting material is used in a pharmaceuticaauthorized to be placed on the market within its jurisdwithin another national jurisdiction; and

— the manufacturing site in which a specific starting mproduced is subject to inspections at suitable intervals tothat the manufacturer conforms to GMP as recommeWHO.

1.3.2 The Scheme can also be used by the manufacturer compliance with a quality assurance system (subject to condissuing a certificate as described in section 5 below)

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— its willingness to participate in the scheme;— any significant reservations it intends to observe relatin

participation (i.e. whether it intends to participate activScheme or to use it as a tool); and

— the name and address of its national regulatory authoritycompetent authority.

Documentation on the national system should be provideding on the type of participation.

2.2 A Member State may opt to participate solely to coimportation of pharmaceutical starting materials. This should be stated explicitly in its notification to the WorlOrganization.

2.3 A Member State intending to participate in the Schemeissuing certificates should first satisfy itself that it can meet thing criteria.

• An effective national system is in place to identify the remanufacturers and distributors.

• It can perform inspections according to GMP requconsonant with those recommended by WHO, to which afacturers of pharmaceutical starting materials are req

conform.• It is capable of establishing effective controls to monitor th

of pharmaceutical starting materials manufactured withintry, and has access to an independent quality control labo

• It has a national pharmaceuticals inspectorate, operating of the national drug regulatory authority, and having the competence, experience and resources to assess whether Gother controls are being effectively implemented, and has

power to conduct appropriate investigations to ensure thfacturers conform to these requirements by, for exampleing premises and records and taking samples.

• It has the necessary administrative capacity to issue thecertificates, to institute enquiries in case of complaint, and

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facturing facility. However, should a Member State so wisapproach WHO, or another drug regulatory authority, to occdelegate consultants to act as advisers in the course of nationtions and training activities for inspectors.

3. Requesting a certificate

3.1 A Certificate for Pharmaceutical Starting Materials caquested within the scope of the Scheme by the exporter, imthe competent authority of the importing country.

4. Certificates issued by competent regulatory authoritie

4.1 The proposed formats for these documents are providependices 1 and 2 of these guidelines. For ease of use, these do

are presented in forms suitable for generation by a compparticipating countries are henceforth urged to adopt these ffacilitate the interpretation of certified information. The expnotes that accompany the two documents referred to aboveimportant. Although they are not part of the document to bethey should always be attached to the certificate.

4.2 The certificate should be issued by the competent authoformat proposed in Appendix 1.

The following information should be listed as a minimum: fsee explanatory notes (Appendix 1).

4.2.1 Number of certificate given by the issuing authority.

4.2.2 Exporting (certifying) country.

4.2.3 Importing (requesting) country/countries.

4.2.4 Name of pharmaceutical starting material (Internatioproprietary Names (INNs) should be used whenever possibnatively, national nonproprietary names and/or grades, traand other identifiers, such as official codes, CAS numbers et

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4.2.8. Marketing authorization, licence, Drug Master Filereference(s), such as a certificate of suitability of pharmamonographs with which the starting material complies, as ap

4.2.9 Name and address of applicant for certificate.

4.2.10 Activities of the applicant (e.g. manufacturing, reprelabelling) and, if the applicant is not the original manuprovide the name and address of the original manufacturer

4.2.11 Compliance of facilities and operations with WHOapplicable.

4.2.12 Date of last inspection, if applicable.

4.2.13 Information regarding the certifying authority.

4.2.14 Stamp and date.

4.3 The certificate is a confidential document. As such, issued by the competent authority in the exporting councertifying authority”) only with the permission of the applic

4.4 Once prepared, the certificate is transmitted to the rauthority through the applicant and, when applicable, the agimporting country.

4.5 When any doubt arises about the status or validity of a cthe competent authority in the importing country should rcopy directly from the certifying authority, as provided for i4.2.13 of these guidelines.

4.6 In the absence of any specific agreement to the contrcertificate will be prepared exclusively in the working languthe certifying authority. The applicant will be responsible foing any notarized translation that may be required by the reauthority.

4.7 Since the preparation of certificates imposes a significanistrative load on the certifying authorities, the service may nfinanced by charges levied upon applicants.

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whether or not the document has been issued in the formamended by WHO.

4.11 When the applicant is the manufacturer of the pharmstarting material, the certifying authority should satisfy itseattesting compliance with GMP, that the applicant:

(a) applies identical GMP standards to the pharmaceuticamaterials of all batches manufactured within the faciliting those destined exclusively for export; and

(b) consents, in the event of identification of a quality defenant with the criteria set out, to relevant inspection reporeleased, in confidence, to the competent authority in thof import, should the latter so require.

4.12 When the applicant is not the manufacturer of the pha

cal starting material, the certifying authority should similaritself in so far as it has the authority to inspect the recrelevant activities of the applicant, that it has the applicant’to release relevant reports on the same basis as described i4.11 (b) above.

4.13 Whenever a starting material is purchased through a banother intermediary, or when more than one set of prembeen used for the manufacture and packaging of a starting

the certifying authority should consider whether it has receicient information to satisfy itself that those aspects of the ture of the starting material for which the applicant is noresponsible have been undertaken in compliance with GMP trading and distribution practices (GTDP)a as recommeWHO.

4.14 Each certificate should identify the importing countr

stamped on every page with the official seal of the certifying to avert potential abuse of the Scheme, to frustrate attfalsification, to render routine authentication of certificatindependent authority superfluous and to enable the certithority to maintain comprehensive records of countries to w

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5. Certificates issued by manufacturers

5.1 A manufacturer may issue a certificate, for instance whis no national authority in the exporting country that coulcertificate and/or no legal framework, and provided that thindependent certifying body or competent authority to acompliance with the quality assurance system.

5.2 The certificate of the manufacturer should be accompacopy of the certificate or document issued by the independening body or competent authority.

5.3 The format of the certificate should be as in Appendix

The following information should be listed.

5.3.1 Number of certificate given by the manufacturer.

5.3.2 Exporting country.5.3.3 Importing (requesting) country/countries.

5.3.4 Name of pharmaceutical starting material (use InteNonproprietary Names (INNs) whenever possible; altenational nonproprietary names and/or grades, trademarks aidentifiers, such as official codes, CAS numbers, etc. may b

5.3.5 Complete reference to, and compliance with, pharm

monograph(s), where applicable and/or attached specificati

5.3.6 Whether the pharmaceutical starting material is used maceutical purposes in the exporting country.

5.3.7. Whether the pharmaceutical starting material subjecertificate is used in pharmaceutical products registered for min the exporting country.

5.3.8 Type of product, if applicable.5.3.9 Name and address of manufacturer (issuer of certificluding e-mail address, telephone number and fax number.

5.3.10 (a) Activities of issuer of certificate, e.g. manufacturki d if h i f h ifi i h

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5.3.13 The certificate is based on the information obtained

5.3.13.1 Inspection by competent authority:

— name of competent authority, including e-mail address, tnumber, fax number and name and function of contact p

— date of inspection;— quality assurance system inspected;— standard used for inspection;— result of inspection; and— certificate and supplementary documents to be att

available.

5.3.13.2 Audit by an independent certifying body:

— name of independent certifying body, including e-mail, tnumber, fax number and name and function of contact p

— date of audit;— quality assurance system audited;— standard used for audit;— result of audit; and— certificate and supplementary documents to be att

available.

5.3.14 Name and function of responsible person issuing the s

on behalf of the manufacturer.5.3.15 Date of issue.

5.3.16 Stamp and signature.

The period of validity of the certificate is suggested to be 2

6. Notifying and investigating a quality defect

6.1 Recognizing that the notification of a defect is an iaspect of the quality assurance of starting materials, the turer should have a system in place to notify its customersregulatory authorities of defects that have a potential impaquality and safety of the starting material and to ensure tha

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6.3 It is the responsibility of the Member State adherinScheme to ensure that provisions for carrying out the tasks din 6.1 and 6.2 above are in place.

6.4 In the case of obvious doubt, a participating national may request WHO to assist in providing a list of qualitylaboratories to carry out tests for the purposes of quality co

6.5 Each certifying authority undertakes to inform WHO aas possible, all competent national authorities, of any seriounewly associated with a starting material exported undervisions of the Scheme, or of any criminal abuse of the Scparticular, the export of falsely labelled, spurious, countersubstandard pharmaceutical starting materials. On receipnotification, WHO will immediately inform the competentauthority in each Member State.

6.6 WHO stands prepared to offer advice should any difficin implementing any aspect of the Scheme or in resolving a cobut it cannot be a party to any resulting litigation or arbitra

References

1. WHO Expert Committee on Speci fi cations for Pharmaceutical PrepaThirty-sixth report. Geneva, World Health Organization, 2002 (WHO

Report Series, No. 902).

2. Quality control of drugs. In: Twenty-second World Health Assembly

Massachusetts, 8 – 25 July 1969. Part 1. Resolutions and decisions,

Geneva, World Health Organization, 1969 (Official Records of the W

Health Organization, No. 176): 99–105.

Further reading

Certification scheme on the quality of pharmaceutical starting materials

international commerce. In: Twenty-eighth World Health Assembly, Gen

May 1975. Part 1. Resolutions and decisions, annexes . Geneva, Wo

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WHO Expert Committee on Speci fi cations for Pharmaceutical Preparati

seventh report . Geneva, World Health Organization, 2003 (WHO Techn

Series, No. 908).

WHO certification scheme on the quality of pharmaceutical starting

moving in international commerce. In: Forty- fi rst World Health Assemb

2 – 13 May 1988. Resolutions and decisions, annexes . Geneva, World H

nization, 1988 (Document WHA41/1988/REC/1): 53–55.

Revised drug strategy. In: Fifty-second World Health Assembly, GenMay 1999 . Geneva, World Health Organization, 1999 (Resolution WHA

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Appendix 1Model Certificate for Pharmaceutical StartingMaterials issued by the competent nationalauthority

(Letterhead of issuing authority)

Certificate of a Pharmaceutical Starting Material1

This certificate conforms to the format recommended by the WoOrganization (general instructions and explanatory notes attache

1. Certificate number:____________________________________________________

2. Exporting (certifying) country:____________________________________________________

3. Importing (requesting) countries:____________________________________________________

4. Name of Pharmaceutical Starting Material:2

____________________________________________________

5. Indicate complete reference and compliance with copoeial monograph(s), where applicable and/or specifications:

____________________________________________________

6. Is the Pharmaceutical Starting Material subject to tficate used in pharmaceutical products registered for min the exporting country? yes / no / unknown (kappropriate)

7. If yes, which types of product?3

____________________________________________________

8. Indicate marketing authorization, licence, Drug Masteother reference as applicable:

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(a) manufactures the Pharmaceutical Starting Material;(b) repackages and/or relabels the Pharmaceutical Starting

manufactured by an independent company, or;(c) is involved in none of the above (e.g. distributes, trade(d) manufactures the Pharmaceutical Starting Material an

manufacturing sites may be involved.4

10.2 If answers b, c or d apply, provide name and addremanufacturing site(s):____________________________________________________

11. Does the manufacturer comply with WHO GMP?5

yes / no / not applicable6 (for “no” and “not applicableexplain and specify):

____________________________________________________

12. Date of last inspection, if applicable: ________________I herewith confirm that the data above are valid. Any chacould affect the validity of this certificate shall be notifieapplicant. Under normal circumstances the certificate is vayears.

13. Information regarding the regulatory certifying author

Name and address of certifying competent authority:______________________________________________________________________________________________________

E-mail: _______ Telephone no.: _________ Fax no.: ____

Name and function of responsible person:___________________________________________________

Signature of responsible person:

___________________________________________________

14. Stamp and date:

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General instructions

Please refer to the guidelines for full instructions on how to this form and for information on the implementation of theOnly originals or certified copies will be accepted.

The forms are suitable for generation by computer. Thealways be submitted as hard copy, with responses printed

rather than handwritten.

Additional sheets should be appended, as necessary, to accoremarks and explanations.

Certifying authorities shall indicate the total number of cluded in the certificate and shall number them, e.g. page x

initial every page.

Explanatory notes

(1) This certificate, which is in the format recommended bestablishes the status of the Pharmaceutical Starting Matof the applicant for the certificate in the exporting countra single Pharmaceutical Starting Material only.

(2) Whenever available, use International Nonproprietar(INNs); alternatively, national nonproprietary name

grades, trademarks and other identifiers, such as officiCAS numbers etc. may be used.(3) List the dosage forms and categories. Example given b

Pharmaceutical Product(s)a Category(ies)

Dosage form(s):

Tablets Cytotoxic

Hormone

Penicillin

Injectables Cefalosporin

(4) Specify whether the manufacturer responsible for pl

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(c) is involved in none of the above (e.g. distributes, tr(d) manufactures the pharmaceutical starting mate

further manufacturing sites may be involved.

If the manufacturer is not the original manufacturer, the sibe given.

(5) The requirements for good practices in the manufac

quality control of drugs referred to in the certificate aincluded in Quality assurance of pharmaceuticals: a com

of guidelines and related materials. Good manufacturingand inspection, Volume 2, Updated edition. GenevHealth Organization, 2004.

(6) “Not applicable” means that no legal requirements mplace or implemented for GMP inspection of the PharmStarting Materials for which the certificate is issued.

(7) Including specifications referred to under point 5.

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Appendix 2Model Certificate for Manufacture of PharmacStarting Materials issued by the manufacturer

(Letterhead of the manufacturer )

Certificate of a Pharmaceutical Starting Material1

This certificate conforms to the format recommended by the WoOrganization (general instructions and explanatory notes attache

1. Certificate number:

____________________________________________________2. Exporting country:____________________________________________________

3. Importing country:____________________________________________________

4. Name of Pharmaceutical Starting Material:2

____________________________________________________

5. Indicate complete reference and compliance with pharmmonograph(s) where applicable and/or attached specificatio____________________________________________________

6. Is this Pharmaceutical Starting Material used for pharmpurposes in the exporting country? yes / no / unknown (appropriate)

____________________________________________________

7. Is the Pharmaceutical Starting Material subject to this cused in pharmaceutical products registered for marketinexporting country? yes / no / unknown (key in as appropria

8 If hi h t f d t 3

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State whether the issuer:

(a) manufactures the Pharmaceutical Starting Material;(b) repackages and/or relabels the Pharmaceutical Starting

manufactured by an independent company, or;(c) is involved in none of the above (e.g. distributes, trade(d) manufactures the Pharmaceutical Starting Material an

manufacturing sites may be involved.10.2 If answers a, b, c or d apply, provide name and addremanufacturing site(s):____________________________________________________

11. Main categories of materials produced on site:5

— Pharmaceutical starting materials: ___________________

— Active pharmaceutical ingredients: __________________

— Excipients: ______________________________________

— Cosmetics: _______________________________________

— Foodstuffs: ______________________________________

— Agrochemicals: ___________________________________

— Others (please specify): ___________________________12. Indicate additional regulatory information, such as reflicence, Drug Master File, or other reference as applicable:____________________________________________________

13. Information based on:____________________________________________________

13.1 Inspection by competent authority:

Country: ______________________________________

Name of competent authority: _________________________

E-mail: __________ Telephone no.: __________ Fax no.: __

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13.2 Audit by an independent certifying body:____________________________________________________

Name of independent certifying body: __________________

E-mail: __________ Telephone no.: __________ Fax no.: __

Name and function of contact person: __________________

— date of audit: _____________________________________— quality assurance system audited: ___________________

— standard used for audit: ____________________________

— result of audit: ___________________________________

— attach certificate or supporting document, if available.

14. Name and function of responsible person:

____________________________________________________I herewith confirm that the data above are valid. Any chacould affect the quality of the pharmaceutical starting matthat will change the data on the certificate will be commUnder normal circumstances the certificate is valid for 2 ye

15. Date: ___________________________________________

16. Stamp and signature: _____________________________

Attachments:7

List of documents attached:____________________________________________________

____________________________________________________

General instructions

Please refer to the guidelines for full instructions on how to this form and for information on the implementation of theOnly originals or certified copies of this document will be a

Th f it bl f ti b t Th

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Explanatory notes

(1) This certificate, which is in the format recommended bestablishes the status of the Pharmaceutical Starting Maof the applicant for the certificate in the exporting coufor a single Pharmaceutical Starting Material only.

(2) Whenever available, use International Nonproprietar(INNs); alternatively, national nonproprietary namegrades, trademarks and other identifiers, such as officCAS numbers etc. may be used.

(3) List the dosage forms and categories. Example given b

(4) Specify whether the manufacturer responsible for plPharmaceutical Starting Material on the market:(a) manufactures the Pharmaceutical Starting Materia(b) repackages and/or relabels the Pharmaceutical

Material manufactured by an independent compan(c) is involved in none of the above (e.g. distributes, tr(d) manufactures the pharmaceutical starting mate

further manufacturing sites may be involved.

If the manufacturer is not the original manufacturer, the si

be given.(5) The categories of materials produced on site will give inf

about the profile of the manufacturing site.(6) The requirements for good practices in the manufac

li l f d f d i h ifi

Pharmaceutical Product(s)a Category(ies)

Dosage form(s):

Tablets Cytotoxic

Hormone

Penicillin

Injectables Cefalosporin

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of guidelines and related materials. Good manufacturing

and inspection, Volume 2, Updated edition. GenevHealth Organization, 2004.

(7) Including specifications referred to under point 5.

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Appendix 3Glossary and key words

This glossary explains terms used in these Guidelines and/orrelevant sections. It is intended as supplementary informatioas a formal part of the Scheme. Note that the definitions giv

apply to the terms as used in these Guidelines. They may haent meanings in other contexts.

Applicant

The party applying for a certificate for a pharmaceuticamaterial.

Competent authority

The national regulatory authority in the Member State. Th

tent authority can issue or receive certificates.

Good manufacturing practices (GMP)

That part of quality assurance which ensures that products atently produced and controlled to the quality standards apto their intended use and as required by the marketing auth(In: Quality assurance of pharmaceuticals: a compendium lines and related materials. Good manufacturing practices

spection. Volume 2, Updated edition. Geneva, WorldOrganization, 2004).

GTDP

Good Trade and Distribution Practices (Annex 2, WHO TReport Series, No. 917).

Manufacture

All operations of purchase of materials and starting mater

duction, quality control, release, storage, shipment of finishematerials, and the related controls.

Pharmaceutical starting material

Any substance of a defined quality used in the product

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material by the competent authority of the exporting couintended for use by the competent authority in the importinor in the absence of such an authority by, for example, the turer of the finished product when exporting.

WHO responsibility (see item 6.6 of guidelines above)

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Annex 4Procedure for assessing the acceptability, inprinciple, of quality control laboratories for usUnited Nations agencies

1. Introduction

2. Steps of the procedure

2.1 Publication of Invitation for Expression of Interest

2.2 Submission of submitted laboratory information file

2.3 Screening of submitted laboratory information file

2.4 Assessment of laboratory information file

2.5 Site inspection

2.6 Report and outcome of evaluation

2.7 Results of assessment

2.8 Re-qualification

2.9 Proficiency testing

2.10 Monitoring of complaints

2.11 Cost recovery

2.12 Confidentiality undertaking

2.13 Conflict of interest

Appendix

Provisions for inspectors (team members participating in site visits)

within the scope of the quality assessment procedure of qualitycontrol laboratories

I t d ti

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laboratories to be used for the analysis of pharmaceutical purchased as part of the pre-qualification procedure for including, but not limited to, those for the treatment of HItuberculosis (TB) and malaria. Participation in the pre-quaprocedure is voluntary and any laboratory (private or govercould participate. Certification such as ISO (in terms IEC17025) is encouraged and will also be considered in

qualification procedure. It is recommended that laboratoriwork towards obtaining certification.

The quality assessment procedure established by WHO is the following principles:

— reliance on the information supplied by the national drutory authority;

— a general understanding of the quality control activiti

laboratory;— evaluation of information submitted by the laboratory; — assessment of consistency in quality control through co

with good manufacturing practice(s) and WHO guidelin

WHO should collaborate with national drug regulatory auththe quality assessment. WHO recommends that laboratoriesing their interest in testing drugs on behalf of United Nationsinform the regulatory authorities and other networks (e.g. Otheir intention to be pre-qualified and request the regulatoryties to collaborate with WHO in the quality assessment pro

This procedure provides advice and recommended standaprocess to be followed for pre-qualification of quality controtories by and/or for the United Nations. Many of the recomtions are also relevant to non-United Nations organizations


WHO requires information related to the activities and qut l f d t in l b t i Int t d lit nt l

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WHO will publish an invitation widely in the internatioand on WHO’s web pages, and when necessary repeat it aintervals, to request laboratories to submit an Expression o(EOI) in testing pharmaceutical products on behalf of Uniteagencies. The invitation should be open and transparent, inlaboratories to submit the EOI for the tests listed in the inv

Laboratories should submit their EOI with the relevant infrequested, before the date specified by WHO.

When WHO receives the EOI, it will record the receipt offrom each laboratory in a register.

2.2 Submission of laboratory information file

Each interested laboratory should provide the specified foindicated in the EOI with a laboratory information file (LIF)ing the required information, before a date specified by WH

The information should be submitted as described in the d“Guidelines for preparing a laboratory information file (LIFTechnical Report Series, No. 917, Annex 5) and contain infon the areas listed below:

— general information— documentation— personnel— handling of samples— materials— premises— equipment— quality control— contract operations and activities— out-of-specification investigation— self-inspection— stability testing— microbiological testing

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LIF within a specified time period. In the event that this rnot complied with, the LIF will in principle be rejected on gincompleteness and returned to the laboratory.

LIFs that comply with the format recommended by WHO wretained for evaluation purposes and (2) the laboratory will bered for a possible site inspection (if this is warranted base

outcome of the evaluation of the LIF).

2.4 Assessment of the laboratory information file

The LIF will be evaluated by WHO in accordance with a operating procedure established by WHO for assessing LIsure uniformity in evaluation.

2.5 Site inspection

Dependent on the outcome of the evaluation of the LIF, Wplan and coordinate inspections at the laboratory to assesance with “Good practices for control laboratories” as recomby WHO.1 The inspection will be performed by an inspector of inspectors consisting of experts appointed by WHO, pfrom regulatory authority inspectorates. A WHO staff memcoordinate the team and the team members will act as teexpert advisers to WHO. The inspector or team will per

inspections and report on the findings in accordance with aoperating procedure describing the planning and performaninspections to ensure a standard harmonized approach.

A representative or representatives of the drug regulatory of the country where the laboratory is located would norexpected to accompany the team to the laboratory to assesance with good practices standards.

Evaluators and inspectors must have the relevant qualificaexperience.


Th i i i ill fi li d

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If any additional information is required, or if corrective actibe taken by the laboratory, WHO will postpone its final recotions until the additional information has been evaluatecorrective action has been taken and found satisfactory in ligspecified standards.

In the event of any disagreement between a laboratory and

standard operating procedure for the handling of appeals plaints will be followed to discuss and resolve the issue.

As WHO is responsible for the quality assessment, the ownthe reports lies with WHO (without prejudice, however, to adential and proprietary information of the laboratory conthis report).

2.7 Results of assessmentOnce WHO is satisfied that the quality assessment proceslaboratory is complete, and that the laboratory is acceptablciple for use by United Nations Agencies (i.e. it has been meet the WHO recommended standards), the laboratory at fied site will be included in a list referred to as “List of qualitlaboratories meeting WHO norms and standards”.

Laboratories on the List will be considered to be able to testin compliance with WHO recommended good practices sta

Each laboratory will receive a letter from WHO informingoutcome of the quality assessment process for that particulatory. A copy of this letter will be sent to the national drug rauthority of the country where the laboratory is located.

The List will be compiled in accordance with a standard o

procedure and the List will be subjected to review at least onThe List will be published and will also be included on the Wpage.

There should be an agreement between the organization

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Routine re-quali fi cation

• Re-inspections of laboratories should be made at regularat least once every 3 years.

• Re-evaluation of LIFs should be done every 3 years, oshould any change be implemented by the laboratory.

Non-routine re-quali fi cation

Non-routine re-qualification may be done in the following s

— in case of any omission of information in the initial assesif false or misleading information is suspected during thup assessment;

— if changes are implemented that may have an impact on

qualification of the laboratory, such as changes to key pequipment or testing apparatus, testing method, facilityaspects;

— if a complaint considered to be serious in nature has beenby WHO or one or more of the United Nations ageorganizations;

— WHO may suspend or withdraw a pre-qualified qualitlaboratory from the List when there is evidence

compliance with the predetermined general notes and cor with the good practices for national pharmaceuticalaboratories.

2.9 Proficiency testing

The laboratory should provide evidence of participation in ate proficiency testing schemes.

2.10 Monitoring of complaint(s)

Complaint(s) concerning the results of analysis of pharmproduct(s) or batches of product(s) supplied by the labo

i i id d b th l b t th t

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manufacturing site is located. The drug regulatory authoralso be invited to participate in the investigation of the com

WHO will make a copy of the report available to the laboratoassessment.

2.11 Cost recovery

WHO reserves the right to charge for the quality assessmcedure on a cost recovery basis.


The inspectors will treat all information to which they gaduring the inspections, or otherwise in connection with the of their responsibilities in regard to the above-mentioned pconfidential and proprietary to WHO or parties collabora

WHO in accordance with the terms set forth below and thtained in the attached Provisions for inspectors (team memticipating in site visits) within the scope of the quality asprocedure of laboratories (see Appendix).

Inspectors will take all reasonable measures to ensure:

— that confidential information is not used for any purpothan the inspection activities described in this document

— that confidential information is not disclosed or provideperson who is not bound by similar obligations of confiand non-use as contained herein.

Inspectors will not, however, be bound by any obligations of tiality and non-use to the extent they are clearly able to demthat any part of the confidential information:

— was known to them prior to any disclosure by or on

WHO (including by laboratories); or— was in the public domain at the time of disclosure by or of WHO (including by laboratories); or

— has become part of the public domain through no fault ofhas become available to them from a third party not in

i i k f l i d fli f i d

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is no risk of a real or perceived conflict of interest and deemed appropriate for the inspector in question to underwork, he/she will discharge his/her functions exclusively as aWHO. In this connection, each inspector is required to conthe information disclosed by him/her in the Declaration of Icorrect and that no situation of real, potential or apparent cinterest is known to him/her, including that he/she has no fin

other interest in, and/or relationship with a party, which:

— may have vested commercial interest in obtaining acceconfidential information disclosed to him/her in the couinspection activities described in this document; and/or

— may have a vested interest in the outcome of the inspec

Each inspector will undertake to promptly advise WHOchange in the above circumstances, including if an issue aris

the course of his/her work for WHO.All inspectors furthermore agree, that at the laboratory’sWHO will advise the laboratory in advance of the identityinspector and the composition of the team performing the sition, and provide curricula vitae of the inspectors. The lathen has the opportunity to express possible concerns regaof the inspectors to WHO prior to the visit. If such concerns cresolved in consultation with WHO, the laboratory may obteam member’s participation in the site visit. Such an objectbe made known to WHO by the laboratory within ten days oof the proposed team composition. In the event of such an oWHO reserves the right to cancel its agreement with the iand the activities to be undertaken by that inspector, in whpart.

A di

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AppendixProvisions for inspectors (team membersparticipating in site visits) within the scope ofquality assessment procedure of quality contrlaboratories

In the course of discharging your functions as an expert a

WHO under the attached Agreement for the Performance (APW), you will gain access to certain information, which i

etary to WHO or entities collaborating with WHO, includingratories which need to be assessed as part of the quality as

procedure by WHO. You undertake to treat such informationafter referred to as “the Information”) as confidential and pr

to WHO or the aforesaid parties collaborating with WHOconnection, you agree:

— not to use the Information for any other purpose than dis your obligations under the above-mentioned APW; and

— not to disclose or provide the Information to any person w

bound by similar obligations of confidentiality and non-utained herein.

However, you will not be bound by any obligations of confiand non-use to the extent that you are clearly able to demons

any part of the Information:

(i) was known to you prior to any disclosure by or on

WHO (including by the laboratory(s)); or (ii) was in the public domain at the time of disclosure

behalf of WHO (including the laboratory(s)); or

(iii) becomes part of the public domain through no fau

own; or (iv) becomes available to you from a third party not in

any legal obligations of confidentiality.

You also undertake not to communicate your deliberations

no financial or other interest in and/or other relationship with

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no financial or other interest in, and/or other relationship with

which:

(i) may have a vested commercial interest in obtaining

any part of the Information referred to above; and/o(ii) may have a vested interest in the outcome of the eva

the laboratory.

You undertake to promptly advise WHO of any change in tcircumstances, including if an issue arises during the courswork for WHO.

I hereby accept and agree with the conditions and provistained in this document.

Signed _____________________________________________

Name (typewritten) _________________________________

Institute ____________________________________________

Place ___________________________ Date _____________


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Annex 5Guidelines for preparing a laboratoryinformation file

A laboratory information file (LIF) is a document preparelaboratory. It contains specific and factual information aoperations carried out at the named site and any closely inoperations of the laboratory. If only some of the operationried out on the site, the LIF need describe only those operasampling, chemical analysis or stability testing. The LIF include information specific to environmental managementtional health and safety management, financial managemenmanagement.

A LIF should be succinct and, if possible, should not exceepages.

The laboratory should give a short description of its activiteach of the following headings. Where appropriate, supportmentation should be appended.

1. General information

1.1 Brief information on the laboratory (including name, adcontact details).

1.2 Summary of laboratory activities (including those listed

Activity Performed by Contracted to:laboratory (give name and aitself (mark X)

Conventional

1 3 Any other activities carried out on site In addition

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1.3 Any other activities carried out on site. In addition, relation (if any) to a manufacturing site.

1.4 Short description of the quality management system of ratory (including reference to the existence or not of manual). (Include reference here regarding certification 17025.)

2. Documentation and quality assurance systems

2.1 Brief description of the procedures for the preparationand distribution of necessary documentation for specificatiodard test procedures, analyst workbooks or worksheets.

2.2 Brief description of any other documentation related totesting, including reports, records, arrangements for the haresults (including laboratory information management

(LIMS) where used).

2.3 Procedures for release of certificates and analytical repodard operating procedures, etc.

2.4 Brief description of general policy for validation of methods.

3. Personnel

3.1 Number of employees engaged in the following activiti

Activity Number

Supervisors

Analysts

Technicians

Microbiologists

Other

4. Handling of samples

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g p

4.1 Brief description of general policy for sampling and hasamples.

4.2 Brief description of the procedures followed. Where flow sheets and charts describing important steps, pooling ofstorage, work allocation in the laboratory and related aspec

be supplied.

5. Materials

5.1 Brief description of general policy for purchasing and hamaterials including chemicals and reagents, and handling o

5.2 Brief description of the arrangements for the storage of including retention samples, toxic substances and poisons.

5.3 Brief description of the system for purchasing, preparatdling and testing of reference materials.

6. Premises

6.1 Simple plan or description of the layout of the laboratwith an indication of scale (architectural or engineering drarequired, but photographs may be submitted if available).

6.2 Nature of construction and finishes.

6.3 Brief description of ventilation systems including those fbiological testing areas, storage areas, etc. (Include referencirculation and to control of temperature and relative humi

6.4 Brief description of special areas for the handling of highazardous, and sensitizing materials.

6.5 Description of planned programmes for preventive maiof the premises and the system for recording maintenance a

Sanitation

6 6 B i f d i i f h d f l i f

7. Equipment

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q p

7.1 Brief description of main equipment used in the laboratach a list of equipment in use, in table form, indicating the eand its make and model.

7.2 Brief description of planned programme for the preventtenance of equipment and the system for recording the mai

activities.7.3 Brief description of qualification (e.g. installation qua(IQ), operational qualification (OQ) and performance qua(PQ)) as well as calibration, including the recording system

7.4 Brief description of computer system, access to data, drity management and validation of the computer system.

8. Contract operations and activities

8.1 List of activities contracted out to other laboratories, names, addresses and contact details. Description of thwhich the compliance with standards for activities contractassessed.

9. Out-of-specification investigation

9.1 Brief description of the procedure for recording and inve

of out-of-specification results.

10. Self-inspection

10.1 Brief description of the self-inspection procedure.

11. Stability testing (where applicable)

11.1 Brief description of the stability-testing procedure.

11.2 Brief description of the conditions under which samkept, the arrangements for monitoring and the equipment u

12. Microbiological testing (where applicable)

13. Water system

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13.1 Brief description of the water system in the laboratory

13.2 Brief description of arrangements for the sampling and water used in the laboratory.


WHO Technical Report Series No 917 2003

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Annex 6Procedure for assessing the acceptability, inprinciple, of procurement agencies for use by

United Nations agencies

1. Introduction



2.2 Submission of a procurement agency information file

2.3 Screening of submitted procurement agency information file

2.4 Assessment of procurement agency information file

2.5 Site inspection




2.9 Testing of samples


2.11 Cost recovery



Appendix

Provisions for inspectors (team members participating in site visits)within the scope of the quality assessment procedure of procurement

agencies

1 Introduction

mended by WHO and operate in compliance with relevant pf d h i l

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for good pharmaceutical procurement.

The quality assessment procedure established by WHO is the following principles:

— reliance on the information supplied by the procuremen— general understanding of the activities performed by the

ment agency;— evaluation of information submitted by the procuremenin a procurement agency information file (PAIF);

— assessment of consistency in pre-qualification, purchasinand distribution through compliance with interim guidethe assessment of a procurement agency or a ModeAssurance System (MQAS)1 as recommended by WHO

WHO should collaborate with national authorities in the q

sessment. WHO will advise United Nations agencies of thement agencies that have been found acceptable in principlthrough a procedure of quality assessment based on WHOmended guidelines and standards.


WHO requires information related to the activities of the ment agency to enable it to perform the assessment. Inprocurement agencies provide this information by submitticurement agency information file (PAIF) with the informquested about the procurement agency to WHO. In additievaluation of the information submitted, a site inspection(sperformed. WHO reserves the right to terminate the qualiment procedure of a procurement agency when the proc

agency is not able or fails to provide the required informatia specified time period, or when inadequate information is sucomplete the quality assessment effectively.

In the context of this document, procurement is defined as t


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WHO will publish an invitation widely in the internatioand on its web pages at regular intervals, when necessary, tprocurement agencies to submit an Expression of Interest perform procurement activities on behalf of United Nations The invitation should be open and transparent, inviting anyment agency to submit the EOI for the performance of the

to be listed in the invitation.

Procurement agencies should submit their EOI with theinformation requested before the date specified by WHO.

WHO will receive the EOI and record the receipt of the Eeach procurement agency. Guidelines developed for the suof the PAIF shall then be sent to the interested procurement

2.2 Submission of a procurement agency informationfile

Each interested procurement agency should provide the foindicated in the EOI with a PAIF containing the required infbefore a specified date set by WHO.

The information should be submitted as described in the d“Guidelines for preparing a Procurement Agency Informa(PAIF)”2 and provide the information listed below:

— general information— documentation— personnel— pre-qualification— purchasing— storage— quality control— contract operations and activities— distribution— complaints and recalls— self inspection.

PAIFs that are incomplete will not be considered for evaluaprocurement agency will be informed that an incomplete file

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procurement agency will be informed that an incomplete filereceived, and be requested to complete the file within a specperiod. In the event that this is not complied with, the filprinciple, be rejected on grounds of incompleteness and rethe procurement agency.

PAIFs that comply with the requirements of WHO will b

tained for evaluation purposes and (2) the site will be consia possible inspection (if this is warranted based on the outcoevaluation of the PAIF).

2.4 Assessment of the procurement agency information fi

The PAIF will be evaluated by WHO in accordance with a operating procedure for assessing PAIFs based on the WHlines to ensure uniformity in evaluation.

2.5 Site inspection

Dependent on the outcome of the evaluation of the PAIF, Wplan and coordinate the performance of inspections at thassess compliance with the “Interim guidelines for the asof a procurement agency” or a “Model quality assurance(MQAS)3 as recommended by WHO. The inspection wil

formed by an inspector or a team of inspectors consisting oappointed by WHO. A WHO staff member will coordinateand the team members will act as temporary expert advisers The inspector or inspection team(s) will perform the inspecreport on the findings in accordance with standard operacedures for planning and performing site inspections to standard harmonized approach.

Inspectors must have the relevant qualifications and experi


The inspector or inspection team(s) will finalize a report accthe WHO format describing the findings of the inspection. T

corrective action has been taken and found satisfactory in ligspecified standards

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specified standards.

In the event of any disagreement between a procurement agWHO, a standard operating procedure for the handling oand complaints will be followed to discuss and resolve the i

As WHO is responsible for the quality assessment, the ownthe reports lies with WHO (without prejudice, however, tofidential and proprietary information of the procuremencontained in this report).


Once WHO is satisfied that the quality assessment procesprocurement agency is complete, and that the agency is acceprinciple for use to carry out procurement on behalf of

Nations agency (i.e. it has been found to meet the WHOmended standards), the agency will be included in the “Liscurement agencies meeting the WHO standards”.

Procurement agencies on the list will be considered to be peprocurement activities in compliance with WHO’s recommeterim guidelines for the assessment of a procurement ageMQAS.

Each procurement agency will receive a letter from WHO i

it of the outcome of the quality assessment process in regaparticular activity performed by that procurement agency.

The list will be compiled in accordance with a standard oprocedure for final decision-making for inclusion in the listshould be reviewed and updated at least once a year. The lipublished and will be included on the WHO web page.


Routine re-quali fi cation

• Re-inspections of procurement agencies will be made aintervals at least once every 3 years.

— in case of any omission of information in the initial assesif false or misleading information is suspected during th

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if false or misleading information is suspected during thup assessment;

— if any batch or batches of supplied product(s) are consWHO or one or more of the UN agencies or organizatiobe in compliance with the agreed specification of the praccepted in the dossier as part of the pre-qualification p

for products and manufacturers); or— receipt of a complaint considered to be serious in nWHO or one or more of the United Nations ageorganizations.

Withdrawal and suspension

WHO may suspend or withdraw a pre-qualified procuremefrom the list when there is evidence of noncompliance with

determined general notes and conditions or interim guidelinassessment of a procurement agency or a MQAS.

2.9 Testing of samples

Random samples of pharmaceutical product(s) supplied byment agencies may be taken for independent testing as app

In the event of failure to meet the established criteria

qualification and testing, WHO will investigate the problem municate this to the procurement agency.


Complaint(s) concerning the service provided by the procagency, or a pharmaceutical product(s) or batch of producplied by the procurement agency, communicated to WHOinvestigated in accordance with a standard operating proce

After investigation, WHO will provide a written report anrecommendations for action where relevant.

WHO will make a copy of the report available to the procagency

of their responsibilities in regard to the above-mentioned pconfidential and proprietary to WHO or parties collabora

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p p y pWHO in accordance with the terms set forth below and thtained in the attached Provisions for inspectors (team memticipating in site visits) within the scope of the quality asprocedure of procurement agencies (see Appendix).

Inspectors will take all reasonable measures to ensure:

— that confidential information is not used for any purpthan the inspection activities described in this document

— that it is not disclosed or provided to any person who is nby similar obligations of confidentiality and non-use as cherein.

Inspectors will not, however, be bound by any obligations of tiality and non-use to the extent they are clearly able to dem

that any part of the confidential information:

— was known to them prior to any disclosure by or on WHO (including by procurement agencies); or

— was in the public domain at the time of disclosure by or of WHO (including by procurement agencies); or

— has become part of the public domain through no fault of— has become available to them from a third party not in

any legal obligations of confidentiality.


Before undertaking the work, each inspector will (in additiabove-mentioned confidentiality undertaking) be requiredDeclaration of Interest in accordance with the terms set forand those contained in the attached “Provisions for inspectAppendix). If based on this Declaration of Interest, it is

there is no risk of a real or perceived conflict of interest anddeemed appropriate for the inspector in question to underwork, he/she will discharge his/her functions exclusively as aWHO. In this connection, each inspector is required to con

Each inspector will undertake to promptly advise WHOchange in the above circumstances, including if an issue aris

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g gthe course of his/her work for WHO.

All inspectors furthermore agree, that at the procurementrequest, WHO will advise the procurement agency in advanidentity of each inspector and composition of the team pethe site inspection, and provide curricula vitae of the inspec

procurement agency then has the opportunity to expressconcerns regarding any of the inspectors to WHO prior to thsuch concerns cannot be resolved in consultation with Wprocurement agency may object to a team member’s particithe site visit. Such an objection must be made known to WHprocurement agency within ten days of receipt of the propocomposition. In the event of such an objection, WHO resright to cancel its agreement with the inspector, and the ac

be undertaken by that inspector, in whole or in part.

AppendixProvisions for inspectors (team members

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Provisions for inspectors (team membersparticipating in site visits) within the scope ofquality assessment procedure of procuremenagencies

In the course of discharging your functions as an expert a

WHO under the attached Agreement for the Performance (APW), you will gain access to certain information, which i

etary to WHO or entities collaborating with WHO, includingcurement agencies which need to be assessed as part of th

assessment procedure by WHO. You undertake to treat suchtion (hereinafter referred to as “the Information”) as confide

proprietary to WHO or the aforesaid parties collaborating wi

In this connection, you agree:

— not to use the Information for any other purpose than dis your obligations under the above-mentioned APW; and

— not to disclose or provide the Information to any person w

bound by similar obligations of confidentiality and non-utained herein.

However, you will not be bound by any obligations of confi

and non-use to the extent that you are clearly able to demonsany part of the Information:

(i) was known to you prior to any disclosure by or on

WHO (including by the procurement agency(s)); or(ii) was in the public domain at the time of disclosure

behalf of WHO (including the procurement agency(

(iii) becomes part of the public domain through no fau

own; or (iv) becomes available to you from a third party not in any legal obligations of confidentiality.

You also undertake not to communicate your deliberations

no financial or other interest in, and/or other relationship with

which:

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(i) may have a vested commercial interest in obtaining

any part of the Information referred to above; and/o(ii) may have a vested interest in the outcome of the eva

the procurement agencies.

You undertake to promptly advise WHO of any change in tcircumstances, including if an issue arises during the courswork for WHO.

I hereby accept and agree with the conditions and provistained in this document.

Signed _____________________________________________

Name (typewritten) _________________________________

Institute ___________________________________________

Place _______________________ Date ________________



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Annex 7Guidelines for the preparation of a procuremeagency information file

Introduction

A procurement agency information file (PAIF) is a documpared by the procurement agency (PA) that contains spefactual information about the operations carried out at the nincluding any closely integrated operations of the PA.

A PAIF should be succinct and, if possible, should not exce

pages.

The PA should give a short description of its activities undethe following headings. Where appropriate, supportive dotion should be appended.

1. General information

1.1 Brief information on the PA (including name, address

tact details).1.2 Activities of PA as licensed by the national authority (those listed below). (Attach a copy of the licence. Where a not available, please state reasons.)

Activity Performed by Contracted to:agency (give name and a

itself (mark X) of contractor)

Pre-qualificationof products andm n f t

2. Documentation

2.1 Brief description of procedures for the preparation, rev

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distribution of necessary documentation for pre-qualificatchasing, quality control, storage and distribution.

2.2 Any other documentation related to product quality thmentioned elsewhere in this file.

2.3 Any other activities carried out on the site.

3. Personnel

3.1 Number of employees engaged in the following activiti

Activity Numberemploye

Pre-qualification

Purchasing

Quality control

Storage

Distribution

3.2 Organization chart showing the arrangements for all dep(e.g. quality assurance, including pre-qualification, purchaquality control).

3.3 Qualifications, experience and responsibilities of key pe

3.4 Outline of arrangements for basic and in-service trainingrecords are maintained.

4. Pre-qualification

4.1 Brief description of general policy for pre-qualificationucts manufactured by specific manufacturers.

5. Purchasing

5.1 Brief description of general policy for purchasing.

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5.2 Brief description of purchasing operations and procedu

5.3 Description of tender system used.

6. Storage

6.1 Simple plan or description of storage areas, with indiscale, including receiving, quarantine, returned goods, rejectstorage, staging and dispatch (architectural or engineering not required).

6.2 Nature of construction and finishes.

6.3 Brief description of ventilation systems for storage areference to control of temperature and relative humidity.

6.4 Brief description of special areas for the handling of highazardous and sensitizing materials.

6.5 Brief description of planned programmes for preventivnance of premises and of the system for recording these ac

Equipment

6.6 Provide a list of equipment used in activities.

6.7 Brief description of computer systems used in all opercluding quality control where relevant.

Sanitation

6.8 Brief description of procedures for cleaning.

6.9 Brief description of procedure for rodent and pest cont

7. Handling of materials

7.1 Types of products stored on the site and information aspecifically toxic or hazardous substances handled.

7.5 Brief description of procedure for the handling ofproducts.

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7.6 Brief description of procedure for the handling of products.

8. Distribution

8.1 Brief description of procedure and recording system for

tion of products (including packing for dispatch, handling oous materials, cold chain management etc., where relevant)

8.2 Brief description of procedure for release of proddispatch.

8.3 Brief description of procedure to verify that the recipithorized to receive the product(s).

9. Complaints and product recall

9.1 Brief description of procedures for the handling of coand product recalls.

10. Contract operations and activities

10.1 Brief description of the way in which the compliance wdards for activities that are contracted out is assessed.

10.2 Brief description of the quality control system. (This clude, where relevant, the activities of a quality control labpre-shipment sampling and testing etc.)

11. Self-inspection

11.1 Brief description of the self-inspection system.



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Annex 8Interim guidelines for the assessment of aprocurement agency (based on the draft mode

quality assurance system for procurementagencies)

1. Introduction and background

2. Interim assessment tool for pre-qualification of a procurement agenc

site

1. Introduction and background

WHO has established a procedure describing the procesqualifiying procurement agencies (PAs). PAs interested pre-qualified for possible use by other organizations (incluUnited Nations) will have to submit information about theirfor assessment as part of a pre-qualification procedure. Thistion should be provided in a procurement agency inform(PAIF).

To further harmonize norms and standards in activities in PAin collaboration with other United Nations procurement tions, nongovernmental organizations and interested organizin the process of preparing norms and standards for PAs. Tbe reflected in a model quality assurance system (MQAS).

As the MQAS is not yet available in its final format, an assessment Guideline” has been prepared that can be usedMQAS document is available. The immediate objective oterim assessment guideline is to provide an interim assessmfor the pre-qualification of PAs. It recommends key (interimments for qualit assurance for PAs hich could in principle

Two of the objectives of these Guidelines are to ensure thasuppliers of high-quality products are pre-selected, and thquality assurance programmes involving both surveilla

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q y p g gtesting, are implemented.

It is recommended that:

• Procurement procedures (including pre-qualification of and manufacturers as well as purchasing procedures) stransparent.

• Efficient procedures should be in place to pre-select potepliers and manufacturers, to manage procurement and deensure good quality of the product and to monitor the perof suppliers and manufacturers and of the procurement s

• Written procedures (describing the use of explicit criteriacontracts) should be used throughout the process.

• Pre-qualified and selected products, manufacturers and should be monitored through a process which takes intoproduct quality, service reliability, delivery time and viability.

For the purpose of this interim assessment Guideline, the associated with the PA may include inter alia:

— pre-qualification (product dossier assessment and manusite inspections);

— purchasing;— storage; and— distribution.

A PA could perform all four of the above-mentioned activitsome cases, one or more of the four may be contracted out torganization. In such a case, the PA is still responsible foactivites associated with the procurement or wholesale distri

the products.This interim assesssment Guideline focuses on aspects of tpharmaceutical ingredients and finished pharmaceutical used in the treatment of HIV-related diseases, malaria and tu

An assessment report with the observations recorded shouldmunicated to the PA concerned.

The organization responsible for the interim assessmen

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The organization responsible for the interim assessmendecide whether an organization responsible for some of the(e.g. distribution by a distributor licensed by a national autperform this activity) should be inspected.

2. Interim assessment tool for pre-qualification of aprocurement agency site

This report (based on the checklist) contains confidential infand shall not be divulged to any person other than those mon this page, or without prior consent of the procurement agreport is the property of the organization responsible for pethe inspection.

Part 1: General information about the agency

Name of procurement agency:

Physical address:

Postal address:

Telephone number:Fax number:

E-mail address:

24-hour contact number:

Web page address:

Summary of activities of the agency:

(e.g. pre-qualification, purchasing,storage, distribution). List the names,addresses and contact details of organizations contracted to perform

)

Person responsible for purchasing:

Person responsible for quality assurance:

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Summary and conclusion

Summary: (Provide a brief summary of the findings)

Conclusion:

(Select appropriate option)

Based on the findings of the inspection, and the observationthe inspection report, the procurement agency was found to

ating/not operating ( select option) at an acceptable level oance with the WHO recommendations for quality assurancefor procurement agencies.

Guideline and checklist: procurement agency

Organizational structure

Person responsible for quality control:

Person in charge of distribution/ shipping:

Names of inspectors:

Date of inspection:

Project:

Guidelines C PCThe agency should have an organizational chartindicating key persons in positions of responsibility.

Persons in key positions should have written job

Guidelines C PC

Organizational structure (continued)

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There should be a sufficient number of personswith suitable qualifications and experienceresponsible for storage.

There should be a sufficient number of persons

with suitable qualifications and experienceresponsible for distribution.

The agency should be licensed by the nationalauthority to perform the activities listed above(licence number: _________) (Attach).

There should be a responsible person who isauthorized to perform the activities listed above.

Clarification of observations made:

C, compliant; NA, not applicable; NC, noncompliant; PC, partially compliant

Guidelines C PCThe agency should have a documented qualitypolicy and quality systems should be defined inwriting.

All activities should be defined in clear,unambiguous written procedures.

Records should be maintained for defined periods

of time that ensure traceable actions.Written contracts should exist with otherorganizations (as applicable), for performingactivities on behalf of the agency

Quality assurance

Guidelines C PC

The agency should have procedures for andrecords of the training provided to employees.

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records of the training provided to employees.



Pre-quali fi cation

Guidelines C PC

The procurement agency should follow a writtenpolicy, standards and procedures describing thepre-qualification of products, suppliers and

manufacturers.Product data and information should be requestedfrom manufacturers and be assessed in accordancewith the minimum data and information reflectedin attachment A.

Manufacturers should manufacture their productsin compliance with WHO good manufacturing

practices.Pre-qualification of manufacturers should includeevaluation of evidence of compliance with WHOgood manufacturing practices through assessmentof:

• valid manufacturing licence issued by thecompetent authority; and

• certificate of a pharmaceutical product (WHOtype) issued by the competent authority; and /or

• on-site inspection when necessary.

The pre-qualification of products should be linked

Monitoring of product quality

Guidelines C PC

A person should be responsible for the review of

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A person should be responsible for the review of the certificate of analysis and/or related documentssupplied by the manufacturer for the batches of products.

The review should be carried out in accordancewith a written procedure.

Records for this should be maintained.

The agency should have a written procedure toensure that random samples of shipments aretaken for analysis. The results of the analysisshould be reviewed by a responsible person.

The agency should have access to a laboratory,either their own or one contracted to performanalysis of the samples taken.

A written procedure should be in place to review“out-of-specification” results, including the in-vestigation of these results and appropriate actionto be taken.

The agency should have written procedures for the

detection, identification and handling of counterfeitproducts.

There should be a procedure for handling productcomplaints.



Purchasing

Guidelines C PC

The agency should have written transparent

Guidelines C PC

Internationally accepted principles for purchasingshould be followed. If tenders are used, these

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should be published with specifications for theproducts to be purchased.

The adjudication should be transparent and fair.All decisions should be recorded and records kept.

Procedures and agreements should be in place toensure that the product purchased is the same asthe product that had been pre-qualified.



Storage

(The following key points are a summary of the guidelines Storage Practices referred to in the text under “Introducbackground”.)

Guidelines C PC

PersonnelThere should be an adequate number of suitablyqualified personnel to achieve pharmaceuticalquality assurance objectives at each storage site.National regulations on qualifications should befollowed.

All personnel should receive proper training inrelation to good storage practice, regulations,procedures and safety.

All members of staff should be trained in, andobserve high levels of, personal hygiene and

Storage (continued)

Guidelines C PC

Storage areas should be designed or adapted to

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g g pensure good storage conditions. In particular, theyshould be clean and dry and maintained withinacceptable temperature limits. Where specialstorage conditions are specified on the label (e.g.

for temperature and relative humidity), theseshould be provided, checked, monitored andrecorded. Materials and pharmaceutical productsshould be stored off the floor and suitably spacedto permit cleaning and inspection. Pallets shouldbe kept in a good state of cleanliness and repair.

Storage areas should be clean and free from

accumulated waste and from vermin. A writtensanitation programme should be availableindicating the frequency of cleaning, and themethods to be used to clean the premises andstorage areas. There should also be a writtenprogramme for pest control. The pest-controlagents should be safe, and there should be no riskof contamination of the materials andpharmaceutical products. There should beappropriate procedures for the cleaning up of anyspillage to ensure complete removal of any risk of contamination.

Physical or other equivalent validated (e.g.electronic) segregation should be provided for thestorage of rejected, expired, recalled or returnedmaterials or products. The materials or products,

and storage areas concerned should beappropriately identified.

Materials and pharmaceutical products should bestored in conditions which assure that their quality

Guidelines C PC

Storage requirements

Written instructions and records should be

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available which document all activities in thestorage areas including the handling of expiredstock. These should adequately describe thestorage procedures and define the route of materials and pharmaceutical products andinformation through the organization in the eventof a product recall being required.

Comprehensive records should be maintainedshowing all receipts and issues of materials andpharmaceutical products according to a specifiedsystem, e.g. by batch number.

All containers should be clearly labelled with atleast the name of the material, the batch number,the expiry date or retest date, the specified storageconditions and reference to the pharmacopoeia,where applicable. Unauthorized abbreviations,names or codes should not be used.

Returned goods

Returned goods, including recalled goods, shouldbe handled in accordance with approvedprocedures and records should be kept.

Product recall

There should be a procedure to recall from themarket, promptly and effectively, pharmaceuticalproducts and materials known or suspected to bedefective.



Distribution

Guidelines C PC

Dispatch and transport

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________________ ________________

Inspector’s signature: Date:

Name: __________

Materials and pharmaceutical products should betransported in such a way that their integrity is notimpaired and that suitable storage conditions aremaintained.

Records for dispatch should be retained, stating atleast:

• the date of dispatch• the customer’s name and address• the product description, e.g. name, dosage formand strength (if appropriate), batch number andquantity

The transport should be readily accessible andavailable on request.

There should be a procedure to ensure that theproducts are supplied to authorized recipients only.

Appropriate documentation should accompany theconsignment to the recipient.



AppendixAttachment A: interim assessment guideline fprocurement agencies

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Pharmaceutical product questionnaire

I. Product identification

Active pharmaceutical ingredient(s) (use INN where possib____________________________________________________

Generic name of the product:____________________________________________________

Dosage form:ᮀ Tablets ᮀ Capsules ᮀ Ampoulesᮀ Vial ᮀ Other

Strength per dosage unit:____________________________________________________

Route of administration:ᮀ Oralᮀ Intramuscularᮀ Intᮀ Subcutaneous ᮀ Ot

Pack size:ᮀ 50 ᮀ 100 ᮀ 1000 ᮀ 1000ml ᮀ

Description of primary packaging materials: _____________

Description of secondary packaging materials: ___________

II. Manufacturer of the product

Name, address and activities of the manufacturer(s) (ormanufacturer(s))

Name Physical address Telephone number, Activity

facsimile number and (e.g. packe-mail contact details

Are all sites listed above licensed by the relevant ᮀ Yauthority to perform the activity?

Is the manufacturing site for THIS product ᮀ Ypre-qualified by the Procurement Agency?

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pre qualified by the Procurement Agency?

Has the manufacturing method for each standard ᮀ Ybatch size been validated?

List the standard batch size: __________________________

III. Supplier identification (to be filled in if information is notto that given in answer to question II)

Name: _____________________________________________

Address: _______________________________________________________________________________________________

Telephone number: _________________________________Facsimile number: __________________________________

E-mail contact details: _______________________________

Link with the product:ᮀ Marketing licence holderᮀ Dᮀ Manufacturer ᮀ O

IV. Regulatory situation (licensing status) in the country

manufactureᮀ Product registered and currently marketed

licence no. _______

ᮀ Product registered for marketing in the country of manufanot currently marketed

licence no. _______

ᮀ Product registered for export only licence no. _______

ᮀ Product not registered (please clarify) : _______________

Please attach a Certificate of Pharmaceutical Product accordWHO Certification Scheme (WHO Technical Report Serie

VI. Finished product specifications

ᮀ British Pharmacopoeia; edition ______________________

ᮀ US Pharmacopeia; edition __________________________

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ᮀ International Pharmacopoeia; edition ________________

ᮀ Other: ___________________________________________

Please attach a copy of the finished product specification, iffrom the British Pharmacopoeia, US Pharmacopeia or IntePharmacopoeia specification.

Limits expressed as percentages for the assay of active ingre

ᮀ 95–105% ᮀ 90–110% ᮀ Other: __________

Additional specifications to those in the pharmacopoeia (e.g

tion, syringeability):

____________________________________________________ Attach a copy of the model certificate of analysis for batch r

Are you willing to provide necessary information (analytiod) to enable the tests to be replicated by another qualitlaboratory?

ᮀ Yes ᮀ No

VII. Stability

Stability testing data available: ᮀ Yes ᮀ No

If yes, type and conditions of testing:

ᮀ accelerated testing

ᮀ 40°C/ 75% relative humidity for 6 months

ᮀ other

In the same packaging as specified in point I (p. 1)

ᮀ Yes ᮀ No

Can a stability report be forwarded within one week requested?

ᮀ Yes ᮀ No

Was the stability testing done on a product of the same

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Was the stability testing done on a product of the same manufactured on the same site and packed in the same pmaterial as that for the product that will be supplied?

ᮀYes

ᮀNo

VIII. Label and insert information

Shelf-life:ᮀ 2 yearsᮀ 3 yearsᮀ 4 yearsᮀ 5 yearsother: __________

Storage conditions (e.g. “Do not store above 30 °C — pro

light”):____________________________________________________

____________________________________________________

Language used on label:ᮀ Bilingual English/French

ᮀ Englishᮀ Frenchᮀ Other

Package insert:ᮀ Yes (attach a copy)ᮀ No

IV. Samples

Can free non-returnable samples be obtained upon requeone week of being requested?

ᮀ Yesᮀ No

X. Therapeutic equivalence

ᮀ demonstrated

ᮀ by in vivo bioequivalence studies

Reference product: ________________________________

Number of volunteers: ______________________________

C f d

ᮀ not demonstrated

ᮀ not relevant

ᮀ unknown

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Can a copy of the report be obtained upon request within onbeing requested?

ᮀ Yes ᮀ No

Is the product used in the trial or test essentially the same athat will be supplied (i.e. same materials from the same ssame formula, same manufacturing method)?

ᮀ Yes ᮀ No

XI. Active pharmaceutical ingredient(s) (APIs)

(If more than one active ingredient is used, please supply anthis question separately for each active ingredient used.)

Specifications and standard test methods exist for each excipient:

ᮀ Yes ᮀ No

Each API used (give INN where this exists):

____________________________________________________

ᮀ has a Certificate of suitability to the European Pharm(CEP)

Certificate no.: ____________________________________

ᮀ The CEP is in our possession (including annex if any)

ᮀ The CEP is in the possession of the manufacturer of thproduct (including annex if any).

ᮀ has a Drug Master File (DMF)registered in (country):

ᮀ No pharmacopoeia monograph exists*

*If there is no monograph in a recognized pharmacopoeia,following information should be provided and evaluated:

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Chemical structure

If relevant,

— state the isomeric nature of the active ingredient, includinchemical configuration (e.g. acemate, pure (S)-isomer, 5ture of (Z )- and (E)-isomers);

— the solubility of the active ingredient in water at 25°C o— the solubility of the active ingredient in other solvent

ether, ethanol, acetone and buffers, if different pH (if tingredient is acidic or basic);

— other relevant physicochemical characteristics of the act

dient such as partition coefficient (usually octanol/waterexistence of polymorphs;— copies of infrared, nuclear magnetic resonance (proton

ultraviolet and mass spectra; and— information on the chemical stability of the API, and on

chemical stability if relevant (e.g. formation of a hydratof polymorphic form).

Manufacturer (name, physical address and country):

____________________________________________________

GMP certified: ᮀ Yes (attach a copy of the GMP certifica

Certified by: _________________________

ᮀ No

ᮀ Unknown

XIII. Commitment

I, the undersigned, _________________________________( i i i h G l M A h i

(country of origin), including formulation, method and site facture, sources of active pharmaceutical ingredients and exquality control of the product and starting material, packagilife and product information

ᮀ d I tif th t th d t ff d i id ti l t th t

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ᮀ and I certify that the product offered is identical to that min __________________________________ (name of country____________________________________________________

____________________________________________________(e.g. formulation, method and site of manufacture, sources

pharmaceutical ingredients and excipients, quality control oished product and starting material, packaging, shelf-life, in

product information)

Date: ____________ Signature: ________________

S E L E C T E D W H O P U B L I C A T I O N S O F R E L A T E D I N T E R

Th i t ti l h i hi d di i

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The international pharmacopoeia, third edition.Volume 1: general methods of analysis. 1979 (223 pages)Volume 2: quality specifications. 1981 (342 pages)Volume 3: quality specifications. 1988 (407 pages)Volume 4: tests, methods, and general requirements: quality specificatpharmaceutical substances, excipients and dosage forms. 1994 (358 pagVolume 5: tests and general requirements for dosage forms. Qualityspecifications for pharmaceutical substances and dosage forms. 2003 (3

Basic tests for drugs: pharmaceutical substances, medicinal plant matedosage forms.

1998 (94 pages)

Basic tests for pharmaceutical dosage forms.1991 (134 pages)

Quality assurance of pharmaceuticals: a compendium of guidelines andmaterials.

Volume 1: 1997 (244 pages)Volume 2: good manufacturing practices and inspection. 2004 (236 pag

Quality control methods for medicinal plant materials.

1998 (123 pages)

WHO Expert Committee on Specifications for Pharmaceutical Prepar

Thirty-sixth report.WHO Technical Report Series, No. 902, 2002 (215 pages)

International nonproprietary names (INN) for pharmaceutical substanCumulative list no. 10.

2002 (available in CD-ROM format only)

The use of essential drugs.

Ninth report of the WHO Expert Committee (including the revised Mof Essential Drugs).WHO Technical Report Series, No. 895, 2000 (66 pages)

WHO E t C itt Bi l i l St d di ti

This report presents the recommendations of an internationalgroup of experts convened by the World Health Organizationto consider matters concerning the quality assurance ofpharmaceuticals and specifications for drug substances anddosage forms. Of particular relevance to drug regulatoryauthorities and pharmaceutical manufacturers, this reportdiscusses the latest volume of The International Pharmacopoeia

S P E C I F I C A T I O N S

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i

pand quality specifications for pharmaceutical substances anddosage forms, as well as quality control of reference materials,good manufacturing practices (GMP), inspection, distributionand trade and other aspects of quality assurance of

pharmaceuticals, and regulatory issues.

The report is complemented by a number of annexes, includingrecommendations on good trade and distribution practices forpharmaceutical starting materials, guidelines on the WHOscheme for the certification of pharmaceutical materials movingin international commerce, draft procedures for assessingquality control laboratories and procurement agencies for useby United Nations agencies, and guidelines for preparing alaboratory information file and a procurement agencyinformation file.

F O R P H A

R M A C E U T I C A L P R E P A R A T I O N S

WHOTechnicalReportSeries—917

ISBN 92 4 120917 8